Featured
-
-
Research Briefing |
A protein-templated selection approach for the identification of full ligands from DNA-encoded libraries
A protein-templated selection approach has been developed for the discovery of full ligands from dual-pharmacophore DNA-encoded libraries by incorporating fragment linking into the selection process. The performance of this method was demonstrated with selections against protein–protein interaction and protein–DNA interaction targets, through which potent and selective inhibitors were identified.
-
Article |
Protein-templated ligand discovery via the selection of DNA-encoded dynamic libraries
Dual-pharmacophore DNA-encoded chemical libraries enable the identification of two synergistic binders for a biological target, but subsequent linking of this pair is required to obtain a full ligand, which can be challenging. Here we report a protein-templated selection of DNA-encoded dynamic library that can identify full ligands from fragment libraries without the need for subsequent fragment linking.
- Yu Zhou
- , Wenyin Shen
- & Xiaoyu Li
-
Article |
Molecular jackhammers eradicate cancer cells by vibronic-driven action
In contrast to photothermal therapy requiring high powers over extended times and photodynamic therapy being abrogated by inhibitors of reactive oxygen species, actuation of vibronic modes in single molecules—molecular jackhammers—can now induce efficient cancer cell death. Here, the mechanical disassembly of cell membranes is characterized as the underlying mechanism by which this vibronic-driven action promotes necrotic cell death.
- Ciceron Ayala-Orozco
- , Diego Galvez-Aranda
- & James M. Tour
-
Research Briefing |
In vitro selection of covalent aptamers with sulfur(VI) fluoride exchange chemistry
To develop covalent inhibitors with high potency and low off-target effects, combinatorial approaches that search for candidates from large libraries are desired. Here, sulfur(VI) fluoride exchange (SuFEx) in vitro selection is established for the evolution of covalent aptamers from trillions of SuFEx-modified oligonucleotides. Through this technique, covalent aptamers with optimally balanced selectivity and reactivity are identified.
-
News & Views |
RNA as an off-target for FDA-approved drugs
Medicinal chemistry efforts typically focus on drug–protein interactions and overlook RNA binding as a source of off-target pharmacology. Now, a new method has been developed to map the interactions of small-molecule drugs with RNA in cells and characterize how these interactions can exert functional effects.
- Christopher R. Fullenkamp
- & John S. Schneekloth Jr
-
Article
| Open Access2-Oxabicyclo[2.1.1]hexanes as saturated bioisosteres of the ortho-substituted phenyl ring
The ortho-substituted phenyl ring is a basic structural element in chemistry. Now, 2-oxabicyclo[2.1.1]hexanes have been developed as saturated bioisosteres of the ortho-substituted phenyl ring with improved physicochemical properties. Replacement of the phenyl ring with 2-oxabicyclo[2.1.1]hexanes in marketed agrochemicals fluxapyroxad and boscalid improved water solubility, reduced lipophilicity and retained bioactivity.
- Aleksandr Denisenko
- , Pavel Garbuz
- & Pavel K. Mykhailiuk
-
Article
| Open AccessIn vitro selection of macrocyclic peptide inhibitors containing cyclic γ2,4-amino acids targeting the SARS-CoV-2 main protease
In vitro screening of a ribosomally synthesized macrocyclic peptide library containing cyclic γ2,4-amino acids (cγAA) afforded the discovery of potent inhibitors of the SARS-CoV-2 main protease (Mpro). A co-crystal structure revealed the contribution of this cγAA to Mpro binding and the proteolytic stability of these macrocycles.
- Takashi Miura
- , Tika R. Malla
- & Hiroaki Suga
-
News & Views |
Illuminating anti-ageing
Therapies that destroy senescent cells could be used to alleviate age-related disease, yet conventional drugs often suffer from low selectivity and unwanted side effects. Now, a photosensitive agent has been developed that is activated in situ in senescent cells, enabling their selective elimination.
- Yunjie Xu
- , Jong Seung Kim
- & Mingle Li
-
Article |
Practical synthesis of the therapeutic leads tigilanol tiglate and its analogues
Tigilanol tiglate is a therapeutic lead for the treatment of a broad range of cancers. Now, it has been shown that tigilanol tiglate can be synthesized in a time and step economical fashion from phorbol—its naturally abundant biosynthetic precursor. This synthesis provides rapid access to analogues with unprecedented protein kinase C binding activity.
- Paul A. Wender
- , Zachary O. Gentry
- & Edward Njoo
-
Article |
Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumour eEF1A antagonist SR-A3
The total synthesis and complete stereochemical assignment of the cyclic peptide natural product SR-A3—which has potential as a cancer therapeutic—has now been reported. Single-molecule biophysical and cellular experiments reveal a crucial, stereospecific role for a side-chain hydroxyl in SR-A3, which confers enhanced target residence time and efficacy in a mouse tumour model.
- Hao-Yuan Wang
- , Haojun Yang
- & Jack Taunton
-
Article |
A modular XNAzyme cleaves long, structured RNAs under physiological conditions and enables allele-specific gene silencing
Oligonucleotide catalysts such as ribozymes and DNAzymes can cleave RNA efficiently and specifically but are typically dependent on high concentrations of divalent cations, limiting their biological applications. A modular XNAzyme catalyst composed of 2′-deoxy-2′-fluoro-β-d-arabino nucleic acid (FANA) has now been developed that can cleave long (>5 kb), highly structured mRNAs under physiological conditions and enables allele-specific catalytic RNA knockdown inside cells.
- Alexander I. Taylor
- , Christopher J. K. Wan
- & Philipp Holliger
-
News & Views |
Warhead assembly in a lethal pathogen
Malleicyprols are highly reactive polyketides responsible for virulence in some pathogenic bacteria. Now, the enzyme that constructs the cyclopropanol warhead of malleicyprols has been identified. This enzyme could represent a useful target for developing new antivirulence therapeutics.
- Elijah Abraham
- & Rebecca A. Butcher
-
-
News & Views |
Peptides as molecular Trojan horses
Peptides are a class of versatile biomolecules that function as hormones, signalling messengers and drugs. Now, two papers report alternative approaches to tailor their chemical properties, which enables the transport of biomacromolecules into cells. These approaches could find use in a wide range of biomedical applications.
- Yuan Ping
-
Perspective |
Strategies for developing DNA-encoded libraries beyond binding assays
DNA-encoded libraries can be applied in a diverse range of applications beyond simple binding assays. This Perspective covers the recent progress in using DNA-encoded chemical libraries to investigate complex biological targets and discusses their potential to identify structures that elicit function or possess other useful properties.
- Yiran Huang
- , Yizhou Li
- & Xiaoyu Li
-
News & Views |
A hydroxide lock for metallo-β-lactamases
It is extremely difficult to design a broad-spectrum inhibitor for metallo-β-lactamases (MBLs) due to the diversity in the active site. Now, indole-2-carboxylates have been developed as broad-spectrum inhibitors for MBLs. These inhibitors take advantage of key elements of both MBL substrates and products and work by locking a hydroxide.
- Hongyan Li
- & Hongzhe Sun
-
Article |
Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors
The efficacy of carbapenem antibiotics can be compromised by metallo-β-lactamases, but a high-throughput screen followed by optimization has now enabled the discovery of indole-2-carboxylates (InCs) as potent broad-spectrum metallo-β-lactamase inhibitors. The results highlight the potential of InC–carbapenem combinations for clinical use as well as mechanism-guided approaches to combatting globally disseminated antibiotic resistant mechanisms.
- Jürgen Brem
- , Tharindi Panduwawala
- & Christopher J. Schofield
-
News & Views |
Combining biological and chemical diversity
Phage display enables screening of billions of peptides comprised mainly of natural amino acids. Now, a method to attach and encode a range of structurally diverse compounds has been reported. This method can expand the chemical space covered by phage display peptide libraries.
- Christian Heinis
-
News & Views |
Chemical passports to cross biological borders
The cell membrane acts as a border that restricts uptake of extracellular proteins. Now, peptide chemists have developed two new approaches for transporting functional and biologically relevant proteins across the cellular border by anchoring cyclic polyarginine peptides on the cell membrane.
- Jan Vincent V. Arafiles
- & Shiroh Futaki
-
News & Views |
Expanding the effectiveness of screening
DNA-encoded libraries are a powerful tool to identify hit compounds for drug discovery. Now, two papers have reported new advances in this technology. One paper reports a method to screen for binders inside a living cell, and the other investigates the effects of stereo- and regiochemistry on ligand discovery.
- Minsoo Song
- & Gil Tae Hwang
-
Article |
Stereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications
A DNA-encoded chemical library based on regio- and stereoisomers of phenylalanine has been synthesized and used for affinity-based selections against multiple target proteins. This approach led to the isolation and validation of potent ligands capable of CAR T-cell activation and tumour targeting.
- Nicholas Favalli
- , Gabriele Bassi
- & Dario Neri
-
News & Views |
Designing in vivo active DNAzymes
The therapeutic applications of DNAzymes are limited because of their low effectiveness in vivo. Now, a promising approach for constructing DNAzymes that show high gene-silencing efficiency in mammalian cells has been developed. This approach incorporates chemical modifications into an existing DNAzyme scaffold.
- Yifei Zhou
- & Chuanzheng Zhou
-
Article |
Developing the 134Ce and 134La pair as companion positron emission tomography diagnostic isotopes for 225Ac and 227Th radiotherapeutics
134Ce and 134La have great potential as companion diagnostic isotopes for radiotherapeutics labelled with α-emitting 225Ac and 227Th. Now, by controlling the CeIII/CeIV redox couple, the large-scale production, purification and characterization of 134Ce- and 134La-based radiolabels has been achieved and their use for in vivo positron emission tomography is demonstrated.
- Tyler A. Bailey
- , Veronika Mocko
- & Rebecca J. Abergel
-
News & Views |
Protein targeting with SAF(er) electrophiles
Electrophilic groups that undergo sulfur-exchange chemistry with protein nucleophiles can serve as the functional basis of chemical proteomic probes. A new addition to this class, sulfuramidimidoyl fluoride (SAF), which can be included in an array of covalent small molecule probes, exhibits a unique reactivity profile with proteins.
- Thomas E. Speltz
- & Raymond E. Moellering
-
Article |
Using sulfuramidimidoyl fluorides that undergo sulfur(vi) fluoride exchange for inverse drug discovery
Latent functional groups—typically unreactive unless activated by protein binding—can provide additional selectivity to covalent drugs. Now, compounds containing the weakly electrophilic sulfuramidimidoyl fluoride group, capable of undergoing sulfur(vi) fluoride exchange, have been used to identify reactive proteins in human cell lysate. This approach has identified a compound that conjugates to and inhibits an important anticancer target.
- Gabriel J. Brighty
- , Rachel C. Botham
- & Jeffery W. Kelly
-
Article |
Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms
Screening commercial kinase inhibitors for antibacterial activity identified the anticancer drug sorafenib as a major hit. Subsequent structure–activity optimization created a new antibacterial analogue with high potency against methicillin-resistant Staphylococcus aureus, including challenging persisters and biofilms, as well as demonstrating efficacy in an in vivo mouse model. The mode of action involves stimulation of protein secretion and inhibition of menaquinone biosynthesis.
- Philipp Le
- , Elena Kunold
- & Stephan A. Sieber
-
Article |
Targeted photoredox catalysis in cancer cells
Current photodynamic therapy photosensitizers require oxygen; however, tumours are often hypoxic. Now, an organoiridium complex with an unusually high redox potential, which is effective in normoxia and hypoxia, has been developed. The organoiridium complex kills cancer cells by an immunogenic apoptotic mechanism involving efficient photocatalytic oxidation of NADH to NAD radicals, and reduction of cytochrome c.
- Huaiyi Huang
- , Samya Banerjee
- & Peter J. Sadler
-
Article |
Inhibiting amyloid-β cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design
Inhibiting the interaction between amyloid-β (Aβ) and a neuronal cell surface receptor, LilrB2, could offer a potential route for treating Alzheimer’s disease. Now, binding sites between Aβ and LilrB2 have been discovered and computational selection has identified inhibitors that block this binding site. Cell-penetrating inhibitors were found to block the Aβ–LilrB2 interaction and limit Aβ-induced cytotoxicity.
- Qin Cao
- , Woo Shik Shin
- & Lin Jiang
-
Article |
Chromopynones are pseudo natural product glucose uptake inhibitors targeting glucose transporters GLUT-1 and -3
New natural-product-inspired molecules are often limited by their only partial coverage of biologically relevant chemical space. Combining fragments of natural products has now been shown to yield pseudo natural products, which — while still being inspired by natural products — populate previously unexplored areas of chemical space and have novel biological activities.
- George Karageorgis
- , Elena S. Reckzeh
- & Herbert Waldmann
-
Perspective |
Organic synthesis provides opportunities to transform drug discovery
Organic synthesis is a rate-limiting factor in drug discovery, so the pharmaceutical industry heavily relies on academic research. This Perspective highlights some of the most pressing challenges to be overcome from the industrial viewpoint — such as the development of reactions tolerating specific functionalities — and encourages stronger industry–academia relationships. Credit: Pills image: Profimedia.CZ a.s. / Alamy Stock Photo; Factory image: Diana Johanna Velasquez / Alamy Stock Vector; Graduate hat: Michael Burrell / Alamy Stock Photo; Conical flask: Astex.
- David C. Blakemore
- , Luis Castro
- & Anthony Wood
-
Perspective |
Glucose-responsive insulin by molecular and physical design
Glucose-responsive insulin is a therapeutic that modulates its potency, concentration or dosing relative to a patient’s dynamic glucose concentration. This Perspective summarizes some of the recent accomplishments in this field as well as discussing new computational algorithms that may aid in the development of such therapeutics.
- Naveed A. Bakh
- , Abel B. Cortinas
- & Michael S. Strano
-
Review Article |
The versatility of boron in biological target engagement
Recent years have witnessed a surge of interest in targeted covalent inhibition of disease-associated proteins. Among the electrophiles used to interact with nucleophilic residues in protein structures, boron is unique for its chameleonic ability to display a range of coordination modes upon interaction with protein targets.
- Diego B. Diaz
- & Andrei K. Yudin
-
Article |
Dynamic undocking and the quasi-bound state as tools for drug discovery
Structure-based drug design has generally focused on calculating binding free energies of protein–ligand complexes. It has now been shown that structural, rather than thermodynamic, stability — specifically, the work necessary to reach a quasi-bound state in which the ligand has just broken the most important contact with the receptor — can be calculated and used as a tool in virtual screening.
- Sergio Ruiz-Carmona
- , Peter Schmidtke
- & Xavier Barril
-
Article |
Oxadiazole grafts in peptide macrocycles
Controlling macrocycle conformation represents a powerful tool for the construction of new bioactive molecules. Now, peptide-based macrocycles bearing a 1,3,4-oxadiazole moiety grafted into their backbone have been synthesized via a new cyclization approach. The resulting cyclic products exhibit conformationally rigid turn structures (stabilized through intramolecular hydrogen bonding) that can display passive membrane permeability.
- John R. Frost
- , Conor C. G. Scully
- & Andrei K. Yudin
-
-
Commentary |
Open science is a research accelerator
An open-source approach to the problem of producing an off-patent drug in enantiopure form serves as an example of how academic and industrial researchers can join forces to make new scientific discoveries that could have a huge impact on human health.
- Michael Woelfle
- , Piero Olliaro
- & Matthew H. Todd
-
Editorial |
A bitter pill
Cuts in pharmaceutical R&D jobs might provide short-term improvements to the bottom line, but do not bode well for the industry in the long run.