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Discovery and optimization of pseudopeptide leads towards peptidomimetic drugs

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Summary

Progress in the identification of primary leads is increasingly obtained by the production of molecular diversity via the synthesis of peptide and non-peptide libraries. In this review, statistical considerations are made about the feasibility and reliability of peptide libraries. It is shown that the number of beads per peptide engaged in synthesis controls the relative concentration of any two peptide types, while the total amount of resin determines the feasibility of the complete library in relation to peptide size. Molecular modelling is used to estimate the conformational diversity. A preliminary analysis of libraries by NMR, MS, MS/MS and capillary electrophoresis is advocated. Examples are given of optimized peptide leads in hirudin, neurokinin, bradykinin and angiopeptin series. Finally, the relative effect of hydrogen-bond potential and overall lipophilicity on oral absorption is evaluted on neurokinin-1 and endothelin-1 receptor antagonists.

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  1. Institut de Recherches Servier, 11 rue des Moulineaux, F-92150, Suresnes-Paris, France

    Jean-Luc Fauchère

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Fauchère, JL. Discovery and optimization of pseudopeptide leads towards peptidomimetic drugs. Lett Pept Sci 2, 115–120 (1995). https://doi.org/10.1007/BF00119136

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  • DOI: https://doi.org/10.1007/BF00119136

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