Development of Peptidomimetics with a Vinyl Sulfone Warhead as Irreversible Falcipain-2 Inhibitors

Abstract

This paper describes the synthesis of a new class of peptidomimetic cysteine protease inhibitors based on a 1,4-benzodiazepine scaffold and on an electrophilic vinyl sulfone moiety. The former was introduced internally to a peptide sequence that mimics the fragment D-Ser-Gly; the latter was built on the P1-P1' site and reacts as a classical "Michael acceptor", leading to an alkylated enzyme by irreversible addition of the thiol group of the active site cysteine. The introduction of the vinyl sulfone moiety has been accomplished by olefin cross-metathesis, a powerful tool for the formation of carbon-carbon double bonds. New compounds 2-3 have been proven to be potent and selective inhibitors of falcipain-2, a cysteine protease isolated from Plasmodium falciparum, displaying antiplasmodial activity.

Reversible, Allosteric Small-Molecule Inhibitors of Regulator of G Protein Signaling Proteins

“…The reaction, however, is clearly reversible on the 10-min time scale, and attempts to demonstrate covalent binding by mass spectroscopy have been unsuccessful. Although uncommon, there are other well described examples of reversible Michael acceptor reactions with thiols (Jin et al, 2007;Ettari et al, 2008). Although most drug molecules are designed to avoid such reactive groups, there are a number of examples of clinically used drugs (e.g., omeprazole) or drug candidates [CI-1033;N-[-4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-2-propenamide] that are thiol-reactive (Sachs et al, 1994;Ocañ a and Amir, 2009).…”

Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors

“…These warheads are attached to either a peptidyl or peptidomimetic scaffold 16,41 . We selected cruzain as our primary target due to the high demand for the development of new treatments for Chagas disease.…”

Development of Plasmodium falciparum Protease Inhibitors in the Past Decade (2002–2012)

“…In general, FP inhibitors can be classified in peptidylbased inhibitors (covalent irreversible and reversible inhibitors) [83,90,91], including peptidomimetic compounds [92,93], and nonpeptidic small inhibitors [94][95][96]. …”

“…A common strategy to avoid the therapeutic limitations of peptide-based inhibitors is to lock a defined conformation of the peptide into a rigid scaffold. There are several examples of peptidomimetic inhibitors of FP2 reported in the literature [92,93,[103][104][105][106]. O'Neill and co-workers designed and synthesized novel 2-pyridone peptidomimetic FP2/3 inhibitors with chemical structures shown in (Fig.…”

“…Hence, several groups have developed novel structures where the vinyl sulfone moiety is conserved in an attempt to ensure FP irreversible inhibition. An example of such strategy is that of Zappalà's team [92,93]. These authors synthesized a series of Cys protease inhibitors based on the 1,4-benzodiazepine scaffold, which is known to act as a good mimetic of -turns [113], the structural motif postulated as the biological active form of the D-Ser-Gly peptide [114].…”