Enzyme-free translation of DNA into sequence-defined synthetic polymers structurally unrelated to nucleic acids

Journal name:
Nature Chemistry
Volume:
5,
Pages:
282–292
Year published:
DOI:
doi:10.1038/nchem.1577
Received
Accepted
Published online

Abstract

The translation of DNA sequences into corresponding biopolymers enables the production, function and evolution of the macromolecules of life. In contrast, methods to generate sequence-defined synthetic polymers with similar levels of control have remained elusive. Here, we report the development of a DNA-templated translation system that enables the enzyme-free translation of DNA templates into sequence-defined synthetic polymers that have no necessary structural relationship with nucleic acids. We demonstrate the efficiency, sequence-specificity and generality of this translation system by oligomerizing building blocks including polyethylene glycol, α-(D)-peptides, and β-peptides in a DNA-programmed manner. Sequence-defined synthetic polymers with molecular weights of 26 kDa containing 16 consecutively coupled building blocks and 90 densely functionalized β-amino acid residues were translated from DNA templates using this strategy. We integrated the DNA-templated translation system developed here into a complete cycle of translation, coding sequence replication, template regeneration and re-translation suitable for the iterated in vitro selection of functional sequence-defined synthetic polymers unrelated in structure to nucleic acids.

At a glance

Figures

  1. Natural and laboratory translation of nucleic acids into non-nucleic acid polymers.
    Figure 1: Natural and laboratory translation of nucleic acids into non-nucleic acid polymers.

    a, In living systems, mRNA-templated, tRNA-mediated amine acylation catalysed by the ribosome translates transcripts into sequence-defined proteins. b, Synthetic polymers with non-natural backbones that can be translated from nucleic acid templates by current strategies are all necessarily analogues of DNA and RNA that retain their ability to base-pair with templates. c, The enzyme-free, DNA-templated polymerization strategy developed in this work translates DNA templates into sequence-defined non-nucleic acid polymers. Macrocyclic substrates hybridize with codons on a DNA template, organizing synthetic polymer building blocks along the template. Coupling reactions then oligomerize these pre-organized substrates. Finally, linker cleavage releases the PNA adapters and liberates the synthetic polymer product. d, Representation of a macrocyclic substrate for the translation system in c.

  2. Evaluation of building-block coupling chemistries.
    Figure 2: Evaluation of building-block coupling chemistries.

    a, Translation using AB-type and AA/BB-type substrates. Although both types of substrate can participate in the translation process, AB-type substrates are prone to intramolecular cyclization. b, Denaturing PAGE analysis of translation reactions to evaluate five candidate coupling chemistries. The templates used in lanes 1 and 2 contain eight codons; all other templates contain six codons. The denaturing 10% PAGE–urea gel was electrophoresed in TBE buffer at 200 V for 1 h at room temperature, then stained with ethidium bromide. AA/BB-type substrates coupled by CuAAC offered the highest overall yields of full-length translation products (lanes 16, 18 and 19). In contrast, AB-type substrates failed to yield full-length translation products (lanes 1–8), potentially due to competitive intramolecular cyclization. Notably, the macrocyclic nature of the substrate is required for efficient translation, as non-cyclized substrates showed significantly impaired oligomerization (lanes 20–22). c, Structures of substrates 112, 6s, 12s, 20 and 21. See Supplementary Methods for the structures of 6-uc and 12-uc and reaction conditions.

  3. Identification and analysis of full-length translation products.
    Figure 3: Identification and analysis of full-length translation products.

    a, A fluorescent ‘terminator’ substrate was used to detect full-length translation products. b, Structure of terminator substrates T6-f and T6. c, Dual-channel fluorescent image of a denaturing PAGE analysing translation reactions containing T6-f. Single-stranded DNA was stained with SYBR gold. The coloured rectangles above each lane indicate the arrangement of the codons on the template used in that experiment. The left image shows SYBR gold fluorescence. The right image shows both SYBR gold (green) and Alexa Fluor 647 fluorescence (red). d, Structure of the full-length product with T6 incorporated as the terminator after P1 nuclease digestion. e, MS characterization of the gel-purified full-length product. The left spectrum shows the original multiple charged states of a single molecular species in the ESI analysis, with the numbers indicating the charge of each ion; the right spectrum is deconvoluted from the left spectrum.

  4. Sequence specificity of translation using templates containing mixtures of codons.
    Figure 4: Sequence specificity of translation using templates containing mixtures of codons.

    Each template contains a coding region with six different codons from two codon sets. Every codon from one set is followed by a codon from the other set. Each translation reaction contained five bifunctional AA/BB-type substrates and one terminator substrate. Because incorporation of the terminator ends oligomerization at the codon position in which it is incorporated, polymer lengths reflect the sequence specificity of the translation process.

  5. Translation of DNA sequences into longer polymers and polymers of different backbone structures.
    Figure 5: Translation of DNA sequences into longer polymers and polymers of different backbone structures.

    a, Denaturing PAGE analysis of PEG substrate 6 co-polymerizing with β-peptide substrate 13, PEG substrate 6 co-oligomerizing with α-(D)-peptide substrate 14, substrate 14 co-oligomerizing with α-(D)-peptide substrate 15, and densely functionalized β-peptide substrate 22 co-oligomerizing with densely functionalized β-peptide substrate 23. The DNA template used in these experiments contained six codons, ending with the ‘stop’ codon that recruits the terminator substrate T6 or T7. b, Translation of DNA into longer non-nucleic acid polymers. Translation reactions of DNA templates containing 6, 8, 10, 12, 14 and 16 pentamer codons were performed using substrates 22 and 23. The last codon of each template encoded the incorporation of the Alexa Fluor 647-linked terminator substrate T7-f. The denaturing PAGE was stained with SYBR gold. The green channel shows SYBR gold fluorescence and the red channel shows Alexa Fluor 647 fluorescence. Lanes are marked P6, P8 and so on, reflecting the number of the codons in the template. All lanes contained 10 pmol template for translation reaction. c, Structures of substrates 13, 14, 15, 22 and 23 and terminators T7-f and T7.

  6. A complete cycle of translation, PCR amplification, strand separation and re-translation.
    Figure 6: A complete cycle of translation, PCR amplification, strand separation and re-translation.

    A 100 pmol starting template was translated into synthetic β-peptide polymer using substrates 22, 23 and T7 (lanes 1 and 2). The translation reaction was purified by denaturing PAGE (lane 3). A small amount (1/50,000th) of the translation product, simulating the amount surviving a typical in vitro selection, was subjected to PCR with two primers, generating a double-stranded template (lane 4). The PCR product was immobilized on streptavidin-linked beads and the ‘sense’ strand was eluted with 150 mM NaOH (lane 5). Finally, this single-stranded template was re-translated into synthetic polymer using the same substrates (lane 6). The non-denaturing PAGE gel shown was visualized by ethidium bromide staining. B, biotin; SAv, streptavidin. We note that because the translation product includes a non-nucleic acid synthetic polymer, PAGE mobilities of the DNA template-synthetic polymer conjugates in lanes 2, 3 and 6 are not directly relatable to the molecular weight ladder.

Compounds

42 compounds View all compounds
  1. (S)-2-Amino-N-((S)-3-amino-2-(3-((51S,100S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63,81,87-tris(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-aminobutyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)-3-oxopropyl)-3-hydroxypropanamide
    Compound 1 (S)-2-Amino-N-((S)-3-amino-2-(3-((51S,100S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63,81,87-tris(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-aminobutyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)-3-oxopropyl)-3-hydroxypropanamide
  2. (S)-2-Amino-N-((S)-3-amino-2-(3-((51S,100S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63,81,87-tris(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-(2-(aminooxy)acetamido)butyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)-3-oxopropyl)-3-hydroxypropanamide
    Compound 2 (S)-2-Amino-N-((S)-3-amino-2-(3-((51S,100S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63,81,87-tris(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-(2-(aminooxy)acetamido)butyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)-3-oxopropyl)-3-hydroxypropanamide
  3. (S)-2-Amino-N-((S)-3-amino-2-(3-((51S,100S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63,81,87-tris(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-(2-hydrazinylacetamido)butyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)-3-oxopropyl)-3-hydroxypropanamide
    Compound 3 (S)-2-Amino-N-((S)-3-amino-2-(3-((51S,100S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63,81,87-tris(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-(2-hydrazinylacetamido)butyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)-3-oxopropyl)-3-hydroxypropanamide
  4. (S)-2-(3-((51S,100S)-69,75-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63,81,87-tris(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hept-6-ynamide
    Compound 4 (S)-2-(3-((51S,100S)-69,75-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63,81,87-tris(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hept-6-ynamide
  5. N-((S)-1-Amino-1-oxo-3-(2-oxoacetamido)propan-2-yl)-3-((51S,100S)-81,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-63,69-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-51-((2-oxoacetamido)methyl)-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamide
    Compound 5 N-((S)-1-Amino-1-oxo-3-(2-oxoacetamido)propan-2-yl)-3-((51S,100S)-81,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-63,69-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-51-((2-oxoacetamido)methyl)-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamide
  6. (S)-6-Azido-2-(3-((51S,100S)-81,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-63,69-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hexanamide
    Compound 6 (S)-6-Azido-2-(3-((51S,100S)-81,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-63,69-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hexanamide
  7. (S)-6-Azido-2-(3-((39S,88S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-39-(4-azidobutyl)-51,57-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-88-yl)propanamido)hexanamide
    Compound 6s (S)-6-Azido-2-(3-((39S,88S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-39-(4-azidobutyl)-51,57-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-88-yl)propanamido)hexanamide
  8. (S)-6-Azido-2-(3-((45S,48S)-26,32-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-20-(2-(6-amino-9H-purin-9-yl)acetyl)-48-(4-azidobutyl)-8,14-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,50-nonaoxo-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,49-tetradecaazacyclodopentacontan-45-yl)propanamido)hexanamide
    Compound 6-p0 (S)-6-Azido-2-(3-((45S,48S)-26,32-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-20-(2-(6-amino-9H-purin-9-yl)acetyl)-48-(4-azidobutyl)-8,14-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,50-nonaoxo-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,49-tetradecaazacyclodopentacontan-45-yl)propanamido)hexanamide
  9. (S)-6-Azido-2-(3-((15S,64S)-45,51-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-39-(2-(6-amino-9H-purin-9-yl)acetyl)-15-(4-azidobutyl)-27,33-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-14,17,25,31,37,43,49,55,63,66-decaoxo-1,4,7,10-tetraoxa-20,21,58,59-tetrathia-13,16,24,27,30,33,36,39,42,45,48,51,54,62,65-pentadecaazacyclooctahexacontan-64-yl)propanamido)hexanamide
    Compound 6-p4 (S)-6-Azido-2-(3-((15S,64S)-45,51-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-39-(2-(6-amino-9H-purin-9-yl)acetyl)-15-(4-azidobutyl)-27,33-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-14,17,25,31,37,43,49,55,63,66-decaoxo-1,4,7,10-tetraoxa-20,21,58,59-tetrathia-13,16,24,27,30,33,36,39,42,45,48,51,54,62,65-pentadecaazacyclooctahexacontan-64-yl)propanamido)hexanamide
  10. (S)-6-Azido-2-(3-((15S,64S)-45,51-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-33-(2-(6-amino-9H-purin-9-yl)acetyl)-15-(4-azidobutyl)-27,39-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-14,17,25,31,37,43,49,55,63,66,82-undecaoxo-1,4,7,10,69,72,75,78-octaoxa-20,21,58,59-tetrathia-13,16,24,27,30,33,36,39,42,45,48,51,54,62,65,81-hexadecaazacyclotetraoctacontan-64-yl)propanamido)hexanamide
    Compound 6-p8 (S)-6-Azido-2-(3-((15S,64S)-45,51-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-33-(2-(6-amino-9H-purin-9-yl)acetyl)-15-(4-azidobutyl)-27,39-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-14,17,25,31,37,43,49,55,63,66,82-undecaoxo-1,4,7,10,69,72,75,78-octaoxa-20,21,58,59-tetrathia-13,16,24,27,30,33,36,39,42,45,48,51,54,62,65,81-hexadecaazacyclotetraoctacontan-64-yl)propanamido)hexanamide
  11. N-((S)-6-Amino-5-(3-((39S,88S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-39-(1-azido-15-oxo-3,6,9,12-tetraoxa-16-azaicosan-20-yl)-51,57-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-88-yl)propanamido)-6-oxohexyl)-1-azido-3,6,9,12-tetraoxapentadecan-15-amide
    Compound 7 N-((S)-6-Amino-5-(3-((39S,88S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-39-(1-azido-15-oxo-3,6,9,12-tetraoxa-16-azaicosan-20-yl)-51,57-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-88-yl)propanamido)-6-oxohexyl)-1-azido-3,6,9,12-tetraoxapentadecan-15-amide
  12. (S)-6-Amino-2-(3-((51S,100S)-81,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-69-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-aminobutyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hexanamide
    Compound 8 (S)-6-Amino-2-(3-((51S,100S)-81,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-69-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-aminobutyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hexanamide
  13. (S)-6-(2-(Aminooxy)acetamido)-2-(3-((51S,100S)-81,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-69-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-(2-(aminooxy)acetamido)butyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hexanamide
    Compound 9 (S)-6-(2-(Aminooxy)acetamido)-2-(3-((51S,100S)-81,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-69-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-(2-(aminooxy)acetamido)butyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hexanamide
  14. (S)-2-(3-((51S,100S)-81,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-69-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-(2-hydrazinylacetamido)butyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)-6-(2-hydrazinylacetamido)hexanamide
    Compound 10 (S)-2-(3-((51S,100S)-81,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-69-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-(2-hydrazinylacetamido)butyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)-6-(2-hydrazinylacetamido)hexanamide
  15. (S)-2-(3-((51S,100S)-81,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-69-(2-(6-amino-9H-purin-9-yl)acetyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-51-(4-(pent-4-ynamido)butyl)-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)-6-(pent-4-ynamido)hexanamide
    Compound 11 (S)-2-(3-((51S,100S)-81,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-69-(2-(6-amino-9H-purin-9-yl)acetyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-51-(4-(pent-4-ynamido)butyl)-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)-6-(pent-4-ynamido)hexanamide
  16. N-((S)-6-Amino-5-(3-((39S,88S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-57-(2-(6-amino-9H-purin-9-yl)acetyl)-51,63-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-39-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-88-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
    Compound 12 N-((S)-6-Amino-5-(3-((39S,88S)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-57-(2-(6-amino-9H-purin-9-yl)acetyl)-51,63-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-39-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-88-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
  17. (S)-2-(3-((27S,76S)-57,63-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-45-(2-(6-amino-9H-purin-9-yl)acetyl)-39,51-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-26,29,37,43,49,55,61,67,75,78-decaoxo-27-(4-(3-(prop-2-yn-1-yloxy)propanamido)butyl)-1,4,7,10,13,16,19,22-octaoxa-32,33,70,71-tetrathia-25,28,36,39,42,45,48,51,54,57,60,63,66,74,77-pentadecaazacyclooctacontan-76-yl)propanamido)-6-(3-(prop-2-yn-1-yloxy)propanamido)hexanamide
    Compound 12s (S)-2-(3-((27S,76S)-57,63-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-45-(2-(6-amino-9H-purin-9-yl)acetyl)-39,51-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-26,29,37,43,49,55,61,67,75,78-decaoxo-27-(4-(3-(prop-2-yn-1-yloxy)propanamido)butyl)-1,4,7,10,13,16,19,22-octaoxa-32,33,70,71-tetrathia-25,28,36,39,42,45,48,51,54,57,60,63,66,74,77-pentadecaazacyclooctacontan-76-yl)propanamido)-6-(3-(prop-2-yn-1-yloxy)propanamido)hexanamide
  18. (S)-2-(3-((45S,48S)-26,32-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-14-(2-(6-amino-9H-purin-9-yl)acetyl)-8,20-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,50-nonaoxo-48-(4-(3-(prop-2-yn-1-yloxy)propanamido)butyl)-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,49-tetradecaazacyclodopentacontan-45-yl)propanamido)-6-(3-(prop-2-yn-1-yloxy)propanamido)hexanamide
    Compound 12-p0-s (S)-2-(3-((45S,48S)-26,32-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-14-(2-(6-amino-9H-purin-9-yl)acetyl)-8,20-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,50-nonaoxo-48-(4-(3-(prop-2-yn-1-yloxy)propanamido)butyl)-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,49-tetradecaazacyclodopentacontan-45-yl)propanamido)-6-(3-(prop-2-yn-1-yloxy)propanamido)hexanamide
  19. N-((S)-6-Amino-5-(3-((45S,48S)-26,32-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-14-(2-(6-amino-9H-purin-9-yl)acetyl)-8,20-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,50-nonaoxo-48-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,49-tetradecaazacyclodopentacontan-45-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
    Compound 12-p0-L N-((S)-6-Amino-5-(3-((45S,48S)-26,32-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-14-(2-(6-amino-9H-purin-9-yl)acetyl)-8,20-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,50-nonaoxo-48-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,49-tetradecaazacyclodopentacontan-45-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
  20. (S)-2-(3-((15S,64S)-45,51-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-33-(2-(6-amino-9H-purin-9-yl)acetyl)-27,39-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-14,17,25,31,37,43,49,55,63,66-decaoxo-15-(4-(3-(prop-2-yn-1-yloxy)propanamido)butyl)-1,4,7,10-tetraoxa-20,21,58,59-tetrathia-13,16,24,27,30,33,36,39,42,45,48,51,54,62,65-pentadecaazacyclooctahexacontan-64-yl)propanamido)-6-(3-(prop-2-yn-1-yloxy)propanamido)hexanamide
    Compound 12-p4-s (S)-2-(3-((15S,64S)-45,51-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-33-(2-(6-amino-9H-purin-9-yl)acetyl)-27,39-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-14,17,25,31,37,43,49,55,63,66-decaoxo-15-(4-(3-(prop-2-yn-1-yloxy)propanamido)butyl)-1,4,7,10-tetraoxa-20,21,58,59-tetrathia-13,16,24,27,30,33,36,39,42,45,48,51,54,62,65-pentadecaazacyclooctahexacontan-64-yl)propanamido)-6-(3-(prop-2-yn-1-yloxy)propanamido)hexanamide
  21. N-((S)-6-Amino-5-(3-((15S,64S)-45,51-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-33-(2-(6-amino-9H-purin-9-yl)acetyl)-27,39-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-14,17,25,31,37,43,49,55,63,66-decaoxo-15-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,4,7,10-tetraoxa-20,21,58,59-tetrathia-13,16,24,27,30,33,36,39,42,45,48,51,54,62,65-pentadecaazacyclooctahexacontan-64-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
    Compound 12-p4-L N-((S)-6-Amino-5-(3-((15S,64S)-45,51-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-33-(2-(6-amino-9H-purin-9-yl)acetyl)-27,39-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-14,17,25,31,37,43,49,55,63,66-decaoxo-15-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,4,7,10-tetraoxa-20,21,58,59-tetrathia-13,16,24,27,30,33,36,39,42,45,48,51,54,62,65-pentadecaazacyclooctahexacontan-64-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
  22. N-((S)-6-Amino-5-(3-((27S,76S)-57,63-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-45-(2-(6-amino-9H-purin-9-yl)acetyl)-39,51-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-26,29,37,43,49,55,61,67,75,78-decaoxo-27-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,4,7,10,13,16,19,22-octaoxa-32,33,70,71-tetrathia-25,28,36,39,42,45,48,51,54,57,60,63,66,74,77-pentadecaazacyclooctacontan-76-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
    Compound 12-p8-L N-((S)-6-Amino-5-(3-((27S,76S)-57,63-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-45-(2-(6-amino-9H-purin-9-yl)acetyl)-39,51-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-26,29,37,43,49,55,61,67,75,78-decaoxo-27-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,4,7,10,13,16,19,22-octaoxa-32,33,70,71-tetrathia-25,28,36,39,42,45,48,51,54,57,60,63,66,74,77-pentadecaazacyclooctacontan-76-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
  23. N-((S)-6-Amino-5-(3-((45S,96S)-26,32-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-14-(2-(6-amino-9H-purin-9-yl)acetyl)-8,20-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,51,55,59,63,67,71,75,79,83,87,91,95,98-henicosaoxo-96-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,50,54,58,62,66,70,74,78,82,86,90,94,97-hexacosaazacyclohectan-45-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
    Compound 13 N-((S)-6-Amino-5-(3-((45S,96S)-26,32-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-14-(2-(6-amino-9H-purin-9-yl)acetyl)-8,20-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,51,55,59,63,67,71,75,79,83,87,91,95,98-henicosaoxo-96-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,50,54,58,62,66,70,74,78,82,86,90,94,97-hexacosaazacyclohectan-45-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
  24. 3-((7S,19R,31R,34R,46R,58S)-88,94-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-76-(2-(6-amino-9H-purin-9-yl)acetyl)-46-benzyl-7-((S)-25-carbamoyl-19,27-dioxo-4,7,10,13,16-pentaoxa-20,26-diazanonacos-1-yn-29-yl)-31-isobutyl-19-methyl-70,82-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,68,74,80,86,92,98-pentacosaoxo-58-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,2,63,64-tetrathia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,67,70,73,76,79,82,85,88,91,94,97-triacontaazacyclohectan-34-yl)propanoic acid
    Compound 14 3-((7S,19R,31R,34R,46R,58S)-88,94-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-76-(2-(6-amino-9H-purin-9-yl)acetyl)-46-benzyl-7-((S)-25-carbamoyl-19,27-dioxo-4,7,10,13,16-pentaoxa-20,26-diazanonacos-1-yn-29-yl)-31-isobutyl-19-methyl-70,82-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,68,74,80,86,92,98-pentacosaoxo-58-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,2,63,64-tetrathia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,67,70,73,76,79,82,85,88,91,94,97-triacontaazacyclohectan-34-yl)propanoic acid
  25. (S)-6-Azido-2-(3-((7S,19R,31R,34R,46R,58S)-88,94-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-82-(2-(6-amino-9H-purin-9-yl)acetyl)-34-(4-aminobutyl)-58-(4-azidobutyl)-46-(cyclohexylmethyl)-31-isobutyl-19-methyl-70,76-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,68,74,80,86,92,98-pentacosaoxo-1,2,63,64-tetrathia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,67,70,73,76,79,82,85,88,91,94,97-triacontaazacyclohectan-7-yl)propanamido)hexanamide
    Compound 15 (S)-6-Azido-2-(3-((7S,19R,31R,34R,46R,58S)-88,94-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-82-(2-(6-amino-9H-purin-9-yl)acetyl)-34-(4-aminobutyl)-58-(4-azidobutyl)-46-(cyclohexylmethyl)-31-isobutyl-19-methyl-70,76-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,68,74,80,86,92,98-pentacosaoxo-1,2,63,64-tetrathia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,67,70,73,76,79,82,85,88,91,94,97-triacontaazacyclohectan-7-yl)propanamido)hexanamide
  26. (S)-6-Azido-2-(3-((51S,100S)-81,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-69,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hexanamide
    Compound 16 (S)-6-Azido-2-(3-((51S,100S)-81,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-69,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hexanamide
  27. N-((S)-6-Amino-5-(3-((39S,88S)-57,69-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-51-(2-(6-amino-9H-purin-9-yl)acetyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-39-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-88-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
    Compound 17 N-((S)-6-Amino-5-(3-((39S,88S)-57,69-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-51-(2-(6-amino-9H-purin-9-yl)acetyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-39-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-88-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
  28. (S)-6-Azido-2-(3-((51S,100S)-69,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-63,81-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hexanamide
    Compound 18 (S)-6-Azido-2-(3-((51S,100S)-69,87-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-63,81-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamido)hexanamide
  29. N-((S)-6-Amino-5-(3-((39S,88S)-51,69-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-57,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-39-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-88-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
    Compound 19 N-((S)-6-Amino-5-(3-((39S,88S)-51,69-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-57,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-39-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-88-yl)propanamido)-6-oxohexyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
  30. 3,3'-((51S,100S)-81,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-63,69-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectane-51,100-diyl)dipropanoic acid
    Compound 20 3,3'-((51S,100S)-81,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-63,69-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectane-51,100-diyl)dipropanoic acid
  31. 3-((51S,100S)-69,75-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63,81,87-tris(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-aminobutyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanoic acid
    Compound 21 3-((51S,100S)-69,75-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63,81,87-tris(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-aminobutyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanoic acid
  32. 3,3'-((45S,49S,53R,57S,61S,65S,69S,72S)-61-((1H-Indol-3-yl)methyl)-45-(3-(((S)-1-amino-6-azido-1-oxohexan-2-yl)amino)-3-oxopropyl)-26,32-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-20-(2-(6-amino-9H-purin-9-yl)acetyl)-49-(4-aminobutyl)-72-(4-azidobutyl)-69-benzyl-53-isopropyl-8,14-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,51,55,59,63,67,71,74-pentadecaoxo-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,50,54,58,62,66,70,73-icosaazacyclohexaheptacontane-57,65-diyl)dipropanoic acid
    Compound 22 3,3'-((45S,49S,53R,57S,61S,65S,69S,72S)-61-((1H-Indol-3-yl)methyl)-45-(3-(((S)-1-amino-6-azido-1-oxohexan-2-yl)amino)-3-oxopropyl)-26,32-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-20-(2-(6-amino-9H-purin-9-yl)acetyl)-49-(4-aminobutyl)-72-(4-azidobutyl)-69-benzyl-53-isopropyl-8,14-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,51,55,59,63,67,71,74-pentadecaoxo-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,50,54,58,62,66,70,73-icosaazacyclohexaheptacontane-57,65-diyl)dipropanoic acid
  33. 3-((45S,49R,53S,57S,61R,65S,69S,72S)-45-(3-(((S)-1-Amino-1-oxo-6-(3-(prop-2-yn-1-yloxy)propanamido)hexan-2-yl)amino)-3-oxopropyl)-26,32-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-14-(2-(6-amino-9H-purin-9-yl)acetyl)-65-(4-aminobutyl)-69-benzyl-57-(4-hydroxybenzyl)-49,61-diisopropyl-8,20-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,51,55,59,63,67,71,74-pentadecaoxo-72-(4-(3-(prop-2-yn-1-yloxy)propanamido)butyl)-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,50,54,58,62,66,70,73-icosaazacyclohexaheptacontan-53-yl)propanoic acid
    Compound 23 3-((45S,49R,53S,57S,61R,65S,69S,72S)-45-(3-(((S)-1-Amino-1-oxo-6-(3-(prop-2-yn-1-yloxy)propanamido)hexan-2-yl)amino)-3-oxopropyl)-26,32-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-14-(2-(6-amino-9H-purin-9-yl)acetyl)-65-(4-aminobutyl)-69-benzyl-57-(4-hydroxybenzyl)-49,61-diisopropyl-8,20-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-6,12,18,24,30,36,44,47,51,55,59,63,67,71,74-pentadecaoxo-72-(4-(3-(prop-2-yn-1-yloxy)propanamido)butyl)-1,2,39,40-tetrathia-5,8,11,14,17,20,23,26,29,32,35,43,46,50,54,58,62,66,70,73-icosaazacyclohexaheptacontan-53-yl)propanoic acid
  34. (47S,102S)-1-Amino-102-(3-(((S)-1-amino-6-azido-1-oxohexan-2-yl)amino)-3-oxopropyl)-11,17-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-23-(2-(6-amino-9H-purin-9-yl)acetyl)-47-(4-azidobutyl)-29,35-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-7,13,19,25,31,37,45,48,100-nonaoxo-52,55,58,61,64,67,70,73,76,79,82,85,88,91,94,97-hexadecaoxa-3,4,41,42-tetrathia-8,11,14,17,20,23,26,29,32,35,38,46,49,101-tetradecaazatrihectan-103-oic acid
    Compound 6-uncyc (47S,102S)-1-Amino-102-(3-(((S)-1-amino-6-azido-1-oxohexan-2-yl)amino)-3-oxopropyl)-11,17-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-23-(2-(6-amino-9H-purin-9-yl)acetyl)-47-(4-azidobutyl)-29,35-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-7,13,19,25,31,37,45,48,100-nonaoxo-52,55,58,61,64,67,70,73,76,79,82,85,88,91,94,97-hexadecaoxa-3,4,41,42-tetrathia-8,11,14,17,20,23,26,29,32,35,38,46,49,101-tetradecaazatrihectan-103-oic acid
  35. (50S,93S)-14,20-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-32-(2-(6-amino-9H-purin-9-yl)acetyl)-93-((S)-25-carbamoyl-19,27-dioxo-4,7,10,13,16-pentaoxa-20,26-diazanonacos-1-yn-29-yl)-26,38-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-2,10,16,22,28,34,40,48,51,91-decaoxo-50-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-55,58,61,64,67,70,73,76,79,82,85,88-dodecaoxa-6,7,44,45-tetrathia-3,11,14,17,20,23,26,29,32,35,38,41,49,52,92-pentadecaazatetranonacontan-94-oic acid
    Compound 12-uncyc (50S,93S)-14,20-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-32-(2-(6-amino-9H-purin-9-yl)acetyl)-93-((S)-25-carbamoyl-19,27-dioxo-4,7,10,13,16-pentaoxa-20,26-diazanonacos-1-yn-29-yl)-26,38-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-2,10,16,22,28,34,40,48,51,91-decaoxo-50-(19-oxo-4,7,10,13,16-pentaoxa-20-azatetracos-1-yn-24-yl)-55,58,61,64,67,70,73,76,79,82,85,88-dodecaoxa-6,7,44,45-tetrathia-3,11,14,17,20,23,26,29,32,35,38,41,49,52,92-pentadecaazatetranonacontan-94-oic acid
  36. 3-((51S,100S)-81,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-63,69-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamide
    Compound T1 3-((51S,100S)-81,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-63,69-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamide
  37. N-(4-((39S,88S)-88-(3-Amino-3-oxopropyl)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-57-(2-(6-amino-9H-purin-9-yl)acetyl)-51,63-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-39-yl)butyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
    Compound T2 N-(4-((39S,88S)-88-(3-Amino-3-oxopropyl)-69,75-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-57-(2-(6-amino-9H-purin-9-yl)acetyl)-51,63-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-39-yl)butyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
  38. 3-((51S,100S)-81,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-69,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamide
    Compound T3 3-((51S,100S)-81,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-69,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamide
  39. N-(4-((39S,88S)-88-(3-Amino-3-oxopropyl)-57,69-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-51-(2-(6-amino-9H-purin-9-yl)acetyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-39-yl)butyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
    Compound T4 N-(4-((39S,88S)-88-(3-Amino-3-oxopropyl)-57,69-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-51-(2-(6-amino-9H-purin-9-yl)acetyl)-63,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-39-yl)butyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
  40. 3-((51S,100S)-69,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-63,81-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamide
    Compound T5 3-((51S,100S)-69,87-Bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-75-(2-(6-amino-9H-purin-9-yl)acetyl)-51-(4-azidobutyl)-63,81-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-50,53,61,67,73,79,85,91,99,102-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34,37,40,43,46-hexadecaoxa-56,57,94,95-tetrathia-49,52,60,63,66,69,72,75,78,81,84,87,90,98,101-pentadecaazacyclotetrahectan-100-yl)propanamide
  41. N-(4-((39S,88S)-88-(3-Amino-3-oxopropyl)-51,69-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-57,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-39-yl)butyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
    Compound T6 N-(4-((39S,88S)-88-(3-Amino-3-oxopropyl)-51,69-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-63-(2-(6-amino-9H-purin-9-yl)acetyl)-57,75-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-38,41,49,55,61,67,73,79,87,90-decaoxo-1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxa-44,45,82,83-tetrathia-37,40,48,51,54,57,60,63,66,69,72,75,78,86,89-pentadecaazacyclodononacontan-39-yl)butyl)-4,7,10,13,16-pentaoxanonadec-18-yn-1-amide
  42. N-(4-((15S,64S)-64-(3-Amino-3-oxopropyl)-27,45-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-39-(2-(6-amino-9H-purin-9-yl)acetyl)-33,51-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-14,17,25,31,37,43,49,55,63,66-decaoxo-1,4,7,10-tetraoxa-20,21,58,59-tetrathia-13,16,24,27,30,33,36,39,42,45,48,51,54,62,65-pentadecaazacyclooctahexacontan-15-yl)butyl)-3-(prop-2-yn-1-yloxy)propanamide
    Compound T7 N-(4-((15S,64S)-64-(3-Amino-3-oxopropyl)-27,45-bis(2-(2-amino-6-oxo-1H-purin-9(6H)-yl)acetyl)-39-(2-(6-amino-9H-purin-9-yl)acetyl)-33,51-bis(2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)-14,17,25,31,37,43,49,55,63,66-decaoxo-1,4,7,10-tetraoxa-20,21,58,59-tetrathia-13,16,24,27,30,33,36,39,42,45,48,51,54,62,65-pentadecaazacyclooctahexacontan-15-yl)butyl)-3-(prop-2-yn-1-yloxy)propanamide

References

  1. Badi, N. & Lutz, J-F. Sequence control in polymer synthesis. Chem. Soc. Rev. 38, 33833390 (2009).
  2. Lutz, J-F. Polymer chemistry: a controlled sequence of events. Nature Chem. 2, 8485 (2010).
  3. Pfeifer, S. & Lutz, J-F. A facile procedure for controlling monomer sequence distribution in radical chain polymerizations. J. Am. Chem. Soc. 129, 95429543 (2007).
  4. Nakatani, K., Ogura, Y., Koda, Y., Terashima, T. & Sawamoto, M. Sequence-regulated copolymers via tandem catalysis of living radical polymerization and in situ transesterification. J. Am. Chem. Soc. 134, 43734383 (2012).
  5. Soeriyadi, A. H., Boyer, C., Nyström, F., Zetterlund, P. B. & Whittaker, M. R. High-order multiblock copolymers via iterative Cu(0)-mediated radical polymerizations (SET-LRP): toward biological precision. J. Am. Chem. Soc. 133, 1112811131 (2011).
  6. Lo, P. K. & Sleiman, H. F. Nucleobase-templated polymerization: copying the chain length and polydispersity of living polymers into conjugated polymers. J. Am. Chem. Soc. 131, 41824183 (2009).
  7. McHale, R., Patterson, J. P., Zetterlund, P. B. & Reilly, R. K. O. Biomimetic radical polymerization via cooperative assembly of segregating templates. Nature Chem. 4, 491497 (2012).
  8. Belowich, M. E. et al. Positive cooperativity in the template-directed synthesis of monodisperse macromolecules. J. Am. Chem. Soc. 134, 52435261 (2012).
  9. Lutz, J-F. Sequence-controlled polymerizations: the next Holy Grail in polymer science? Polym. Chem. 1, 5562 (2010).
  10. Leitzel, J. C. & Lynn, D. G. Template-directed ligation: from DNA towards different versatile templates. Chem. Rev. 1, 5362 (2001).
  11. Ura, Y., Beierle, J. M., Leman, L. J., Orgel, L. E. & Ghadiri, M. R. Self-assembling sequence-adaptive peptide nucleic acids. Science 325, 7377 (2009).
  12. Li, X., Zhan, Z-Y. J., Knipe, R. & Lynn, D. G. DNA-catalyzed polymerization. J. Am. Chem. Soc. 124, 746747 (2002).
  13. Schrum, J. P., Ricardo, A., Krishnamurthy, M., Blain, J. C. & Szostak, J. W. Efficient and rapid template-directed nucleic acid copying using 2′-amino-2′3′-dideoxyribonucleoside-5′-phosphorimidazolide monomers. J. Am. Chem. Soc. 131, 1456014570 (2009).
  14. Henry, A. & Romesberg, F. E. The evolution of DNA polymerases with novel activities. Curr. Opin. Biotechnol. 16, 370377 (2005).
  15. Josephson, K., Hartman, M. C. T. & Szostak, J. W. Ribosomal synthesis of unnatural peptides. J. Am. Chem. Soc. 127, 1172711735 (2005).
  16. Datta, B. & Schuster, G. B. DNA-directed synthesis of aniline and 4-aminobiphenyl oligomers: programmed transfer of sequence information to a conjoined polymer nanowire. J. Am. Chem. Soc. 130, 29652973 (2008).
  17. Rosenbaum, D. M. & Liu, D. R. Efficient and sequence-specific DNA-templated polymerization of peptide nucleic acid aldehydes. J. Am. Chem. Soc. 125, 1392413925 (2003).
  18. Kleiner, R. E., Brudno, Y., Birnbaum, M. E. & Liu, D. R. DNA-templated polymerization of side-chain-functionalized peptide nucleic acid aldehydes. J. Am. Chem. Soc. 130, 46464659 (2008).
  19. Peng, X., Li, H. & Seidman, M. A template-mediated click-click reaction: PNA–DNA, PNA–PNA (or peptide) ligation, and single nucleotide discrimination. Eur. J. Org. Chem. 2010, 41944197 (2010).
  20. Chen, W. & Schuster, G. B. DNA-programmed modular assembly of cyclic and linear nanoarrays for the synthesis of two-dimensional conducting polymers. J. Am. Chem. Soc. 134, 840843 (2012).
  21. He, Y. & Liu, D. R. Autonomous multistep organic synthesis in a single isothermal solution mediated by a DNA walker. Nature Nanotech. 5, 778782 (2010).
  22. Mckee, M. L. et al. Programmable one-pot multistep organic synthesis using DNA junctions. J. Am. Chem. Soc. 134, 11461149 (2011).
  23. Brudno, Y., Birnbaum, M. E., Kleiner, R. E. & Liu, D. R. An in vitro translation, selection and amplification system for peptide nucleic acids. Nature Chem. Biol. 6, 148155 (2010).
  24. Yu, H., Zhang, S. & Chaput, J. C. Darwinian evolution of an alternative genetic system provides support for TNA as an RNA progenitor. Nature Chem. 4, 183187 (2012).
  25. Pinheiro, V. B. et al. Synthetic genetic polymers capable of heredity and evolution. Science 336, 341344 (2012).
  26. Driggers, E. M., Hale, S. P., Lee, J. & Terrett, N. K. The exploration of macrocycles for drug discovery—an underexploited structural class. Nature Rev. Drug Discov. 7, 608624 (2008).
  27. Li, X. & Liu, D. R. DNA-templated organic synthesis: nature's strategy for controlling chemical reactivity applied to synthetic molecules. Angew. Chem. Int. Ed. 43, 48484870 (2004).
  28. Hud, N. V., Jain, S. S., Li, X. & Lynn, D. G. Addressing the problems of base pairing and strand cyclization in template-directed synthesis: a case for the utility and necessity of 'molecular midwives' and reversible backbone linkages for the origin of proto-RNA. Chem. Biodiv. 4, 768783 (2007).
  29. Winnik, A. End-to-end cyclization of polymer chains. Acc. Chem. Res. 18, 7379 (1985).
  30. Kolb, H. C., Finn, M. G. & Sharpless, K. B. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. 40, 20042021 (2001).
  31. Lallana, E., Riguera, R. & Fernandez-Megia, E. Reliable and efficient procedures for the conjugation of biomolecules through Huisgen azide–alkyne cycloadditions. Angew. Chem. Int. Ed. 50, 87948804 (2011).
  32. Schmidt, J. G., Christensen, L., Nielsen, P. E. & Orgel, L. E. Information transfer from DNA to peptide nucleic acids by template-directed syntheses. Nucleic Acids Res. 25, 47924796 (1997).
  33. Boehler, C., Nielsen, P. E. & Orgel, L. E. Template switching between PNA and RNA oligonucleotides. Nature 376, 578581 (1995).
  34. Goodwin, J. T. & Lynn, D. G. Template-directed synthesis: use of a reversible reaction. Chem. Commun. 91979198 (1992).
  35. Gartner, Z. J., Kanan, M. W. & Liu, D. R. Expanding the reaction scope of DNA-templated synthesis. Angew. Chem. Int. Ed. 783, 17961800 (2002).
  36. Cho, B. R., Cho, N. S., Song, K. S., Son, K. N. & Kim, Y. K. Elimination reactions of (E)-2,4-dinitrobenzaldehyde O-aryloximes promoted by RO–/ROH buffers in EtOH. J. Org. Chem. 2, 30063009 (1998).
  37. Kumar, R. et al. Template-directed oligonucleotide strand ligation, covalent intramolecular DNA circularization and catenation using click chemistry. J. Am. Chem. Soc. 129, 68596864 (2007).
  38. Chouikhi, D., Barluenga, S. & Winssinger, N. Clickable peptide nucleic acids (cPNA) with tunable affinity. Chem. Commun. 46, 54765478 (2010).
  39. Wright, M. C. & Joyce, G. F. Continuous in vitro evolution of catalytic function. Science 276, 614617 (1997).
  40. Joyce, G. F. Nonenzymatic template-directed synthesis of informational macromolecules. Cold Spring Harb. Symp. Quant. Biol. 52, 4151 (1987).
  41. Daguer, J. P. et al. DNA-templated combinatorial assembly of small molecule fragments amenable to selection/amplification cycles. Chem. Sci. 2, 625632 (2011).
  42. Andersen, C. S., Yan, H. & Gothelf, K. V. Bridging one helical turn in double-stranded DNA by templated dimerization of molecular rods. Angew. Chem. Int. Ed. 47, 55695572 (2008).
  43. El-Sagheer, A. H. & Brown, T. Click chemistry with DNA. Chem. Soc. Rev. 39, 13881405 (2010).
  44. Petersson, E. J. & Schepartz, A. Toward β-amino acid proteins: design, synthesis, and characterization of a fifteen kilodalton β-peptide tetramer. J. Am. Chem. Soc. 130, 821823 (2008).
  45. Goodman, C. M., Choi, S., Shandler, S. & DeGrado, W. F. Foldamers as versatile frameworks for the design and evolution of function. Nature Chem. Biol. 3, 252262 (2007).
  46. Martinek, T. A. & Fulop, F. Side-chain control of β-peptide secondary structures. Design principles. Eur. J. Biochem. 270, 36573666 (2003).
  47. Frackenpohl, J., Arvidsson, P. I., Schreiber, J. V. & Seebach, D. The outstanding biological stability of β- and γ-peptides toward proteolytic enzymes: an in vitro investigation with fifteen peptidases. ChemBioChem 2, 445455 (2001).
  48. Bautista, A. D., Appelbaum, J. S., Craig, C. J., Michel, J. & Schepartz, A. Bridged beta(3)-peptide inhibitors of p53–hDM2 complexation: correlation between affinity and cell permeability. J. Am. Chem. Soc. 132, 29042906 (2010).
  49. Olsen, C. et al. Antimicrobial, hemolytic, and cytotoxic activities of β-peptoid-peptide hybrid oligomers: improved properties compared to natural AMPs. ChemBioChem 11, 13561360 (2010).
  50. Chan, T. R., Hilgraf, R., Sharpless, K. B. & Fokin, V. V. Polytriazoles as copper(I)-stabilizing ligands in catalysis. Org. Lett. 6, 28532855 (2004).

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Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Jia Niu,
    • Ryan Hili &
    • David R. Liu

Contributions

J.N., R.H. and D.R.L. designed the research, analysed the data and co-wrote the manuscript. J.N. performed the experiments.

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The authors declare no competing financial interests.

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