Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Antibody-enabled small-molecule drug discovery

Nature Reviews Drug Discovery volume 11, pages 519–525 (2012)Cite this article

Subjects

Abstract

Although antibody-based therapeutics have become firmly established as medicines for serious diseases, the value of antibodies as tools in the early stages of small-molecule drug discovery is only beginning to be realized. In particular, antibodies may provide information to reduce risk in small-molecule drug discovery by enabling the validation of targets and by providing insights into the design of small-molecule screening assays. Moreover, antibodies can act as guides in the quest for small molecules that have the ability to modulate protein–protein interactions, which have traditionally only been considered to be tractable targets for biological drugs. The development of small molecules that have similar therapeutic effects to current biologics has the potential to benefit a broader range of patients at earlier stages of disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structures of antibody-stabilized G protein-coupled receptors.
Figure 2: Antibody-enabled small-molecule fragment screening and elaboration.

Similar content being viewed by others

References

  1. Ramani, A. K., Bunescu, R. C., Mooney, R. J. & Marcotte, E. M. Consolidating the set of known human protein–protein interactions in preparation for large-scale mapping of the human interactome. Genome Biol. 6, R40 (2005).

    Article  Google Scholar 

  2. Wells, J. A. & McClendon, C. L. Reaching for high-hanging fruit in drug discovery at protein–protein interfaces. Nature 450, 1001–1009 (2007).

    Article  CAS  Google Scholar 

  3. Arkin, M. R. & Wells, J. A. Small-molecule inhibitors of protein–protein interactions: progressing towards the dream. Nature Rev. Drug Discov. 3, 301–317 (2004).

    Article  CAS  Google Scholar 

  4. Dickens, M. P., Fitzgerald, R. & Fischer, P. M. Small-molecule inhibitors of MDM2 as new anticancer therapeutics. Semin. Cancer Biol. 20, 10–18 (2010).

    Article  CAS  Google Scholar 

  5. Gandhi, L. et al. Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J. Clin. Oncol. 29, 909–916 (2011).

    Article  CAS  Google Scholar 

  6. Shuker, S. B., Hajduk, P. J., Meadows, R. P. & Fesik, S. W. Discovering high affinity ligands for proteins: SAR by NMR. Science 274, 1531–1534 (1996).

    Article  CAS  Google Scholar 

  7. Hajduk, P. J. & Greer, J. A decade of fragment-based drug design: strategic advances and lessons learned. Nature Rev. Drug Discov. 6, 211–219 (2007).

    Article  CAS  Google Scholar 

  8. Jhoti, H. Fragment-based drug discovery using rational design. Ernst Schering Found. Symp. Proc. 3, 169–185 (2007).

    Google Scholar 

  9. Murray, C. W. & Rees, D. C. The rise of fragment-based drug discovery. Nature Chem. 1, 187–192 (2009).

    Article  CAS  Google Scholar 

  10. Valkov, E., Sharpe, T., Marsh, M., Grieve, S. & Hyvönen, M. Targeting protein–protein interactions and fragment-based drug discovery. Top. Curr. Chem. 317, 145–179 (2012).

    Article  CAS  Google Scholar 

  11. Sun, C., Petros, A. M. & Hajduk, P. J. Fragment-based lead discovery: challenges and opportunities. J. Comput. Aided Mol. Des. 25, 607–610 (2011).

    Article  CAS  Google Scholar 

  12. Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genet. 34, 154–156 (2003).

    Article  CAS  Google Scholar 

  13. Seidah, N. G. & Prat, A. The biology and therapeutic targeting of the proprotein convertases. Nature Rev. Drug Discov. 11, 367–383 (2012).

    Article  CAS  Google Scholar 

  14. Crunkhorn, S. PCSK9 antibody reduces LDL cholesterol. Nature Rev. Drug Discov. 11, 11 (2012).

    Article  CAS  Google Scholar 

  15. Paalanen, M. M. I. et al. The development of activating and inhibiting camelid VHH domains against human protein kinase C epsilon. Eur. J. Pharm. Sci. 42, 332–339 (2011).

    Article  CAS  Google Scholar 

  16. Haque, A., Anderson, J. N., Salmeen, A., Barford, D. & Tonks, N. K. Conformation-sensing antibodies stabilize the oxidized form of PTP1B and inhibit its phosphatase activity. Cell 147, 185–198 (2011).

    Article  CAS  Google Scholar 

  17. Visintin, M., Melchionna, T., Cannistraci, I. & Cattaneo, A. In vivo selection of intrabodies specifically targeting protein–protein interactions: a general platform for an 'undruggable' class of disease targets. J. Biotechnol. 135, 1–15 (2008).

    Article  CAS  Google Scholar 

  18. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).

    Article  CAS  Google Scholar 

  19. DeLano, W. L. Unraveling hot spots in binding interfaces: progress and challenges. Curr. Opin. Struct. Biol. 12, 14–20 (2002).

    Article  CAS  Google Scholar 

  20. Ganesan, R. et al. Unraveling the allosteric mechanism of serine protease inhibition by an antibody. Structure 17, 1614–1624 (2009).

    Article  CAS  Google Scholar 

  21. Barlow, J. N., Conrath, K. & Steyaert, J. Substrate-dependent modulation of enzyme activity by allosteric effector antibodies. Biochim. Biophys. Acta 1794, 1259–1268 (2009).

    Article  CAS  Google Scholar 

  22. Dong, J. et al. A single domain llama antibody potently inhibits the enzymatic activity of botulinum neurotoxin by binding to the non-catalytic α-exosite binding region. J. Mol. Biol. 397, 1106–1118 (2010).

    Article  CAS  Google Scholar 

  23. Air, G. M., Webster, R. G., Colman, P. M. & Laver, W. G. Distribution of sequence differences in influenza N9 neuraminidase of tern and whale viruses and crystallization of the whale neuraminidase complexed with antibodies. Virology 160, 346–354 (1987).

    Article  CAS  Google Scholar 

  24. Ostermeier, C., Harrenga, A., Ermler, U. & Michel, H. Structure at 2.7Å resolution of the Paracoccus denitrificans two-subunit cytochrome c oxidase complexed with an antibody Fv fragment. Proc. Natl Acad. Sci. USA 94, 10547–10553 (1997).

    Article  CAS  Google Scholar 

  25. Kortt, A. A. et al. Recombinant anti-sialidase single chain variable fragment antibody. Characterisation, formation of dimer and higher-molecular-mass multimers and the solution of the crystal structure of the single-chain variable fragment/sialidase complex. Eur. J. Biochem. 221, 151–157 (1994).

    Article  CAS  Google Scholar 

  26. Loris, R. et al. Crystal structure of the intrinsically flexible addiction antidote MazE. J. Biol. Chem. 278, 28252–28257 (2003).

    Article  CAS  Google Scholar 

  27. Tereshko, V. et al. Toward chaperone-assisted crystallography: protein engineering enhancement of crystal packing and X-ray phasing capabilities of a camelid single-domain antibody (VHH) scaffold. Protein Sci. 17, 1175–1187 (2008).

    Article  CAS  Google Scholar 

  28. Wu, M. et al. Structures of a key interaction protein from the Trypanosoma brucei editosome in complex with single domain antibodies. J. Struct. Biol. 174, 124–136 (2011).

    Article  CAS  Google Scholar 

  29. Korotkov, K. V., Pardon, E., Steyaert, J. & Hoi, W. G. J. Crystal structure of the N-terminal domain of the secretin GspD from ETEC determined with the assistance of a nanobody. Structure 17, 255–265 (2009).

    Article  CAS  Google Scholar 

  30. Zhou, Y., Morais-Cabral, J. H., Kaufman, A. & MacKinnon, R. Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0Å resolution. Nature 414, 43–48 (2001).

    Article  CAS  Google Scholar 

  31. Lam, A. Y., Pardon, E., Korotkov, K. V., Hol, W. G. & Steyaert, J. Nanobody-aided structure determination of the EpsI:EpsJ pseudopilin heterodimer from Vibrio vulnificus. J. Struct. Biol. 166, 8–15 (2009).

    Article  CAS  Google Scholar 

  32. Iwata, S., Ostermeier, C., Ludwig, B. & Michel, H. Structure at 2.8Å resolution of cytochrome c oxidase from Paracoccus denitrificans. Nature 376, 660–669 (1995).

    Article  CAS  Google Scholar 

  33. Streltsov, V. A., Varghese, J. N., Masters, C. L. & Nuttall, S. D. Crystal structure of the amyloid-β p3 fragment provides a model for oligomer formation in Alzheimer's disease. J. Neurosci. 31, 1419–1426 (2011).

    Article  CAS  Google Scholar 

  34. Pai, J. C. et al. Conversion of scFv peptide-binding specificity for crystal chaperone development. Protein Eng. Des. Sel. 24, 419–428 (2011).

    Article  CAS  Google Scholar 

  35. Prongay, A. J. et al. Preparation and crystallization of a human immunodeficiency virus p24–Fab complex. Proc. Natl Acad. Sci. USA 87, 9980–9984 (1990).

    Article  CAS  Google Scholar 

  36. Hino, T. et al. G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody. Nature 482, 237–240 (2012).

    Article  CAS  Google Scholar 

  37. Rasmussen, S. G. F. et al. Structure of a nanobody-stabilized active state of the β2 adrenoceptor. Nature 469, 175–181 (2011).

    Article  CAS  Google Scholar 

  38. Rizk, S. S. et al. Allosteric control of ligand-binding affinity using engineered conformation-specific effector proteins. Nature Struct. Mol. Biol. 18, 437–444 (2011).

    Article  CAS  Google Scholar 

  39. Domanska, K. et al. Atomic structure of a nanobody-trapped domain-swapped dimer of an amyloidogenic β2-microglobulin variant. Proc. Natl Acad. Sci. USA 108, 1314–1319 (2011).

    Article  CAS  Google Scholar 

  40. Saragovi, H. U. et al. Design and synthesis of a mimetic from an antibody complementarity-determining region. Science 253, 792–795 (1991).

    Article  CAS  Google Scholar 

  41. Sadowsky, J. D. et al. Turning a protein kinase on or off from a single allosteric site via disulphide trapping. Proc. Natl Acad. Sci. USA 108, 6056–6061 (2011).

    Article  CAS  Google Scholar 

  42. Lobato, M. N. & Rabbitts, T. H. Intracellular antibodies and challenges facing their use as therapeutic agents. Trends Mol. Med. 9, 390–396 (2003).

    Article  CAS  Google Scholar 

  43. Oyen, D., Srinivasan, V., Steyaert, J. & Barlow, J. N. Constraining enzyme conformational change by an antibody leads to hyperbolic inhibition. J. Mol. Biol. 407, 138–148 (2011).

    Article  CAS  Google Scholar 

  44. Gao, J., Sidhu, S. S. & Wells, J. A. Two-state selection of conformation-specific antibodies. Proc. Natl Acad. Sci. USA 106, 3071–3076 (2009).

    Article  CAS  Google Scholar 

  45. De Genst, E. J. et al. Structure and properties of a complex of α-synuclein and a single-domain camelid antibody. J. Mol. Biol. 402, 326–343 (2010).

    Article  CAS  Google Scholar 

  46. Lafaye, P., Achour, I., England, P., Duyckaerts, C. & Rougeon, F. Single-domain antibodies recognize selectively small oligomeric forms of amyloid β, prevent Aβ-induced neurotoxicity and inhibit fibril formation. Mol. Immunol. 46, 695–704 (2009).

    Article  CAS  Google Scholar 

  47. Habicht, G. et al. Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Aβ protofibrils. Proc. Natl Acad. Sci. USA 104, 19232–19237 (2007).

    Article  CAS  Google Scholar 

  48. Dumoulin, M. et al. A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme. Nature 424, 783–788 (2003).

    Article  CAS  Google Scholar 

  49. Abskharon, R. N. et al. Crystallization and preliminary X-ray diffraction analysis of a specific VHH domain against mouse prion protein. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Crystallogr. 66, 1644–1646 (2010).

    Article  CAS  Google Scholar 

  50. Mossessova, E., Corpina, R. A. & Goldberg, J. Crystal structure of ARF1*Sec7 complexed with brefeldin A and its implications for the guanine nucleotide exchange mechanism. Mol. Cell 12, 1403–1411 (2003).

    Article  CAS  Google Scholar 

  51. Viaud, J. et al. Structure-based discovery of an inhibitor of Arf activation by Sec7 domains through targeting of protein–protein complexes. Proc. Natl Acad. Sci. USA 104, 10370–10375 (2007).

    Article  CAS  Google Scholar 

  52. Monod, J., Changeux, J. P. & Jacob, F. Allosteric proteins and cellular control systems. J. Mol. Biol. 6, 306–329 (1963).

    Article  CAS  Google Scholar 

  53. Christopoulos, A. Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nature Rev. Drug Discov. 1, 198–210 (2002).

    Article  CAS  Google Scholar 

  54. Gunasekaran, K., Ma, B. & Nussinov, R. Is allostery an intrinsic property of all dynamic proteins? Proteins 57, 433–443 (2004).

    Article  CAS  Google Scholar 

  55. Horn, J. R. & Shoichet, B. K. Allosteric inhibition through core disruption. J. Mol. Biol. 336, 1283–1291 (2004).

    Article  CAS  Google Scholar 

  56. González-Ruiz, D. & Gohlke, H. Targeting protein–protein interactions with small molecules: challenges and perspectives for computational binding epitope detection and ligand finding. Curr. Med. Chem. 13, 2607–2625 (2006).

    Article  Google Scholar 

  57. Ganesan, R., Eigenbrot, C. & Kirchhofer, D. Structural and mechanistic insight into how antibodies inhibit serine proteases. Biochem. J. 430, 179–189 (2010).

    Article  CAS  Google Scholar 

  58. Murray, C. W. & Blundell, T. L. Structural biology in fragment-based drug design. Curr. Opin. Struct. Biol. 20, 497–507 (2010).

    Article  CAS  Google Scholar 

  59. Giannetti, A. M. From experimental design to validated hits: a comprehensive walk-through of fragment lead identification using surface plasmon resonance. Methods Enzymol. 493, 169–218 (2011).

    Article  CAS  Google Scholar 

  60. Perspicace, S. et al. Fragment-based screening using surface plasmon resonance technology. J. Biomol. Screen. 14, 337–349 (2009).

    Article  CAS  Google Scholar 

  61. Hämäläinen, M. D. et al. Label-free primary screening and affinity ranking of fragment libraries using parallel analysis of protein panels. J. Biomol. Screen. 13, 202–209 (2008).

    Article  Google Scholar 

  62. Hajduk, P. J., Meadows, R. P. & Fesik, S. W. NMR-based screening in drug discovery. Q. Rev. Biophys. 32, 211–240 (1999).

    Article  CAS  Google Scholar 

  63. Edink, E. et al. Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis. J. Am. Chem. Soc. 133, 5363–5371 (2011).

    Article  CAS  Google Scholar 

  64. Koldobskaya, Y. et al. A portable RNA sequence whose recognition by a synthetic antibody facilitates structural determination. Nature Struct. Mol. Biol. 18, 100–106 (2011).

    Article  CAS  Google Scholar 

  65. Tickle, S. et al. High-throughput screening for high affinity antibodies. J. Lab. Autom. 14, 303–307 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I am grateful to my colleagues at UCB for stimulating discussion and refinement of ideas.

Author information

Authors and Affiliations

  1. Alastair D. G. Lawson is at UCB, 216 Bath Road, Slough, SL1 4EN, UK. alastair.lawson@ucb.com,

    Alastair D. G. Lawson

Authors
  1. Alastair D. G. Lawson
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

Alastair D. G. Lawson is an employee of UCB, and holds shares and share options in the company.

Related links

Related links

FURTHER INFORMATION

ClinicalTrials.gov website

EvaluatePharma website

Glossary

Allosteric modulation

An allosteric effect (such as inhibition, which is also referred to as non-competitive inhibition) that can result from a change in the shape of an active site when an inhibitor binds at an alternative site.

Apo structure

The ligand-free structure of a protein.

Biological risk

In the context of this article, biological risk is the risk associated with modulating the biology of a specific target: for example, the consequences of inhibiting a particular signalling pathway.

Complementarity determining region 3

(CDR3). A region found within an antibody variable region; the CDR has a highly variable amino acid sequence and confers binding specificity.

Chemical risk

In the context of this article, chemical risk is the risk inherent in the therapeutic molecule itself: for example, its off-target activity as well as its pharmacokinetic and pharmacodynamic profiles.

Chaperone

An auxiliary protein that binds to a target of interest, enhances crystallization, optimizes crystal packing and provides high-quality phasing information.

Fragment-based drug discovery

A method that is used for finding lead compounds in drug discovery. It is based on identifying small chemical fragments, which bind relatively weakly to the biological target, and then either increasing the size of the fragments or combining them to produce a lead compound with a higher affinity and increased potency.

Intrabodies

Antibodies, usually antibody fragments, that bind to targets inside a cell (such as intracellular proteins) and are typically expressed intracellularly.

Protofibrils

Transient structures that are implicated as the toxic species responsible for cell dysfunction and neuronal loss in diseases associated with protein aggregation, such as Alzheimer's disease.

Tethering

A technique in which a disulphide bond is used to stabilize the binding of thiol-containing fragments at a specific site on proteins where a cysteine residue has been engineered.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lawson, A. Antibody-enabled small-molecule drug discovery. Nat Rev Drug Discov 11, 519–525 (2012). https://doi.org/10.1038/nrd3756

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3756

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research