Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3

Angewandte Chemie
Michael WeinmüllerHorst Kessler

Abstract

A highly systematic approach for the development of both orally bioavailable and bioactive cyclic N-methylated hexapeptides as high affinity ligands for the integrin αvβ3 is based on two concepts: a) screening of systematically designed libraries with spatial diversity and b) masking of the peptide charge with a lipophilic protecting group. The key steps of the method are 1) initial design of a combinatorial library of N-methylated analogues of the stem peptide cyclo(d-Ala-Ala5 ); 2) selection of cyclic peptides with the highest intestinal permeability; 3) design of sublibraries with the bioactive RGD sequence in all possible positions; 4) selection of the best ligands for RGD-recognizing integrin subtypes; 5) fine-tuning of the affinity and selectivity by additional Ala to Xaa substitutions; 6) protection of the charged functional groups according to the prodrug concept to regain intestinal and oral permeability; 7) proof of biological effects in mice after oral administration.

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Citations

Mar 13, 2018·Biopolymers·Anamika SharmaFernando Albericio
Aug 26, 2018·Angewandte Chemie·Andreas F B RäderHorst Kessler
Dec 16, 2020·Angewandte Chemie·Maritess ArancilloKevin Burgess
Aug 14, 2020·Chemical Reviews·Rasha JwadLuke Hunter
May 8, 2021·Journal of Medicinal Chemistry·Stefano TomassiLuciana Marinelli
Jul 16, 2019·Journal of Medicinal Chemistry·Isabell KemkerNorbert Sewald
Jan 31, 2020·Journal of Medicinal Chemistry·Yajun Zheng, Katerina Leftheris
Jul 18, 2019·ACS Medicinal Chemistry Letters·Spiros Liras, Kim F Mcclure
May 16, 2019·Chemical Reviews·Patrick G DoughertyDehua Pei

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