Identification of Novel Parasitic Cysteine Protease Inhibitors by Use of Virtual Screening. 2. The Available Chemical Directory

Abstract

The incidence of parasitic infections such as malaria, leishmaniasis, and trypanosomiasis has been steadily increasing. Since the existing chemotherapy of these diseases suffers from lack of safe and effective drugs and/or the presence of widespread drug resistance, there is an urgent need for development of potent, mechanism-based antiparasitic agents against these diseases. Cysteine proteases have been established as valid targets for this purpose. The Available Chemical Directory consisting of nearly 355,000 compounds was screened in silico against the homology models of plasmodial cysteine proteases, falcipain-2, and falcipain-3, to identify structurally diverse non-peptide inhibitors. The study led to identification of 22 inhibitors of parasitic cysteine proteases out of which 18 compounds were active against falcipain-2 and falcipain-3. Eight compounds exhibited dual activity against both enzymes. Additionally, four compounds were found to inhibit L. donovani cysteine protease. While one of the cysteine protease inhibitors also exhibited in vitro antiplasmodial activity with an IC50 value of 9.5 microM, others did not show noticeable antiplasmodial activity up to 20 microM. A model identifying important pharmacophoric features common to the structurally diverse falcipain-2 inhibitors has also been developed. Very few potent non-peptide inhibitors of the parasitic cysteine proteases have been reported so far, and identification of these novel and chemically diverse inhibitors should provide leads to be optimized into candidates to treat protozoal infections.

Inhibition of Plasmodium falciparum Oocyst Production by Membrane-Permeant Cysteine Protease Inhibitor E64d

“…E64d is a broad-spectrum cysteine protease inhibitor, and while it is useful for determination of the functional role of cysteine proteases, it is not specific enough to be used therapeutically. To identify a more specific P. falciparum inhibitor, a number of other compounds are being screened for their abilities to block asexual growth and/or falcipain activity (5,16,22). Several compounds that effectively inhibit recombinant falcipains 2A, 2B, and 3 have been developed and have been tested for their effects on asexual growth, but they have never been screened against sexual stage parasites (10,17,29).…”

Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis

“…New targets for the development of drugs against Leishmania have been studied but are still in the experimental phase. Some of these drugs include the sirtuin family of NAD-dependent deacetylases [103], topoisomerase [104], protease inhibitors [105], and inhibitors of the mevalonate pathway such as terpene nerolidol [106]. In addition, the antiestrogen tamoxifen has shown activity against Leishmania amazonensis and Leishmania chagasi both in vitro and in vivo in experimental models [107,108].…”

Host-Parasite Interactions in Trypanosomiasis: on the Way to an Antidisease Strategy

“…Progress in proteomics and genomics will further allow rapid evolution in the field, as several new proteases are already available in gene databanks. Simultaneously, important efforts are being undertaken for the development of CP-inhibiting molecules for T. congolense, T. brucei brucei, and T. brucei rhodesiense (34,35,48,49,59,82,157).…”