Can Cysteine Protease Cross-Class Inhibitors Achieve Selectivity?

Abstract

Cysteine proteases are important targets for the discovery of novel therapeutics for many human diseases. From parasitic diseases to cancer, cysteine proteases follow a common mechanism, the formation of an encounter complex with subsequent nucleophilic reactivity of the catalytic cysteine thiol group toward the carbonyl carbon of a peptide bond or an electrophilic group of an inhibitor. Modulation of target enzymes occurs preferably by covalent modification, which imposes challenges in balancing cross-reactivity and selectivity. Given the resurgence of irreversible covalent inhibitors, can they impair off-target effects or are reversible covalent inhibitors a better route to selectivity? This Perspective addresses how small molecule inhibitors may achieve selectivity for different cathepsins, cruzain, rhodesain, and falcipain-2. We discuss target- and ligand-based designs emphasizing repurposing inhibitors from one cysteine protease to others.

Mapping the S1 and S1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

“…A variety of studies have been conducted on optimization strategies for the interactions of different classes of inhibitors with the S1, S2 and S3 binding sites of cruzain and related cysteine proteases [13,14,19,20]. Nonetheless, far less is known about the attainable interactions at S1′ for dipeptidyl nitrile inhibitors [21].…”

Mapping the S1 and S1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

“…Despite its ability to rescue mice of a lethal experimental T. cruzi infection and reduce parasite growth in dogs, preclinical safety and toxicology studies revealed substantial side effects of K777 in primates and dogs, even when administered in low doses [10,11]. Current research is being focused on reversible Cz inhibitors, as these are assumed to overcome possible off-target effects [12]. Drug repurposing programs of different pharmaceutical companies have recently put forward reversible inhibitors of Cz as potential drug candidates [13].…”

Design, synthesis and trypanocidal activity of cruzain reversible-covalent inhibitors

“…This enzyme has a high degree of structural identity with the human enzymes cathepsin K, cathepsin L, cathepsin S and high sequence homology with cathepsin B that are involved in many physiological processes (KRAMER; TURK; TURK, 2017). Therefore, the knowledge generated from Cz inhibition can be transposed to its mammalian counterparts and vice-versa (CIANNI et al, 2019). The same concept can be applied to another protozoan parasite CPs recently used as a pharmacological target based on in vitro and in vivo models, as the cysteine protease B of the Leishmania mexicana (LmCPB), the obligate intracellular protozoan parasite that causes the cutaneous form of leishmaniasis (CROFT;COOMBS, 2003;SIQUEIRA-NETO et al, 2018).…”

“…A variety of studies have been conducted on optimization strategies for the interactions of different classes of inhibitors with the S1, S2 and S3 binding sites of cruzain and related cysteine proteases. (see chapter I) CIANNI et al, 2019;SCHMITZ et al, 2019). Nonetheless, far less is known about the possible interactions at S1′ for dipeptidyl nitrile inhibitors.…”

“…Concurrently, even if the reversibility of binding may reduce the risk of adverse effects, irreversible binding can result in prolonged duration of action (GEHRINGER; LAUFER, 2019), as for vinyl sulfone derivatives (K777).Figure 28bshows the most employed warheads for cysteine protease inhibition. Not surprisingly, nitrile is the most widely used warhead in crystallographic structures, followed by vinyl sulfone, halomethyl ketone and epoxysuccinate(CIANNI et al, 2019).…”