Design and Synthesis of Phosphonoproline-Proline Bioisosteric Mimetics of Proline Dimers: Pseudopeptide Constructs as Potential Inhibitors of the Zn-Metalloprotease PPEP‑1 Associated with Clostridioides difficile.

Authors

Erick Ivan Martinez Toto, Sofiane Hocine, Jean-Baptiste Garsi, Paul Skrzypczak, Elena Brunstein, Ulrich Baumann, Stephen Hanessian

Published in

ACS medicinal chemistry letters. Volume 17. Issue 7. Pages 1629-1635. Jul 09, 2026. Epub Jun 11, 2026.

Abstract

The design, synthesis and preliminary inhibitory activity of novel phosphonoproline-proline-containing pseudohexapeptides against PPEP-1, a metalloprotease secreted by Clostridioides difficile, is reported. Remarkably, the P_(R)-configured phosphonoproline-proline hexapeptide bioisostere of the synthetic heptapeptide Ac-EVNPPVP-NH₂ is 1000 times more active than the corresponding P_(S) analogue as measured by a FRET assay, which represents a binding energy of about 12 kJ/mol. Placing an embedded enantiopure phosphonoproline unit to replace a proline within a peptidic construct constitutes a promising venue in the design of proline-containing metalloenzyme inhibitors.

PMID:
42445012
Bibliographic data and abstract were imported from PubMed on 13 Sep 2026.

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