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Screening for peptide drugs from the natural repertoire of biodiverse protein folds

Abstract

Although monoclonal antibody (mAb) drugs targeting protein interactions exist, these therapeutics cannot access intracellular proteins involved in disease complexes. Moreover, mAbs are more difficult to deliver and are frequently associated with a prohibitive 'royalty stack.' Outlined here is an alternative approach based on libraries of natural, highly structured peptides that offers new opportunities for identifying effective, specific inhibitors of protein-protein interactions. Libraries of such peptides (referred to hereafter as phylomers) comprise both random and structured peptides encoded by natural genes of diverse bacterial genomes. Because the number of protein subdomain structures found in nature is limited, diverse libraries containing millions of phylomers constitute virtually all of the available classes of protein fold structures, providing a rich source of peptides that interact specifically and with high affinity to human proteins. This approach may help not only in understanding the implications of each interaction identified within the interactome but also in the development of effective drugs targeted to particular protein functions. Although phylomers are active in animal models, the challenge remains to demonstrate efficacy and safety in a clinical setting.

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Figure 1: Constructing libraries from subdomains encoded by biodiverse genomes.

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Acknowledgements

I am grateful to Wayne Thomas, Prue Hart, John Finlay-Jones, Patrick Holt, Rob Aalberse, Vanessa Cull, Mark Fear, Richard Hopkins, Nadia Milech Graham Robertson, Frank Sotzik and laboratory colleagues for assisting with review of the manuscript. The assistance of Graham Carter (Accuro Biologics Ltd) in conducting the bioinformatics analysis of potential for immunogenicity of phylomer peptides is also gratefully acknowledged.

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Correspondence to Paul M Watt.

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P.W. is the scientific director of Phylogica, Ltd., the company that is commercializing the Phylomer technology. P.W. holds both shares and stock options in this company, which is publicly listed on the Australian Stock Exchange (ASX:PYC). This holding amounts to less than 5% of issued capital.

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Watt, P. Screening for peptide drugs from the natural repertoire of biodiverse protein folds. Nat Biotechnol 24, 177–183 (2006). https://doi.org/10.1038/nbt1190

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