Organic synthesis of dipeptidic compounds as human cysteine cathepsins and matrix metalloproteinases inhibitors.

• Grant number: 25/14353-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2025
• End date: May 31, 2026
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Andrei Leitão
• Grantee: Maria Clara Cardoso Sarkis
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 23/16111-8 - Design, synthesis, and characterization of molecular mechanisms of dipeptidyl nitrile derivatives inhibitors of cysteine cathepsins with antineoplastic activity, AP.R

Abstract

Dipeptidyl nitrile derivatives have demonstrated selective activity toward cysteine cathepsins over other macromolecular targets. In a previous computational study, additional macromolecules were analyzed, and it was hypothesized that replacing the nitrile reactive group with a hydroxamic acid moiety would yield compounds selective for matrix metalloproteases. Accordingly, this research project will employ a targeted synthetic strategy to produce six peptidomimetic compounds - three containing nitrile groups and three containing hydroxamic acid groups as reactive warheads. Following purification and structural characterization, these compounds will undergo enzymatic and cellular assays conducted by collaborating researchers to evaluate the validity of the initial hypothesis. This synthetic medicinal chemistry project aims to expand the chemical-biological space by transitioning from cysteine protease to matrix metalloprotease inhibitors, which possess potential antineoplastic activity.