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Greenbaum, D.C. et al. A role for the protease falcipain 1 in host cell invasion by the human malaria parasite. Science 298, 2002-2006

Department of Pharmaceutical Chemistry, Veterans Affairs Medical Center, University of California, San Francisco, CA 94143, USA.
Science (Impact Factor: 33.61). 01/2003; 298(5600):2002-6. DOI: 10.1126/science.1077426
Source: PubMed

ABSTRACT

Cysteine proteases of Plasmodium falciparum are required for survival of the malaria parasite, yet their specific cellular functions remain unclear. We used a chemical
proteomic screen with a small-molecule probe to characterize the predominant cysteine proteases throughout the parasite life
cycle. Only one protease, falcipain 1, was active during the invasive merozoite stage. Falcipain 1–specific inhibitors, identified
by screening of chemical libraries, blocked parasite invasion of host erythrocytes, yet had no effect on normal parasite processes
such as hemoglobin degradation. These results demonstrate a specific role for falcipain 1 in host cell invasion and establish
a potential new target for antimalarial therapeutics.

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    • "Expansion of Hb-specific proteases in this family is less distinct. Even though Plasmodium falcipains are clustered together, Hb-specific falcipains 2 and 3 are separated from invasion-specific falcipain 1 (Fig. 3and Additional file 3: Figure S1)[28,29]. Plasmodium berghei and P. yoelii have two falcipain homologues dichotomically grouped with falcipains 1 and 2 (Fig. 3). "

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    • "An independent study showed 70–90% lower oocyst production in FP1 knockout parasites than wild type parasites, suggesting a key role for FP1 during parasite development in the mosquito midgut [13]. Contrary to the FP1 gene knockout studies, a FP1 specific inhibitor apparently inhibited invasion of erythrocytes by P. falciparum merozoites, suggesting a crucial role of FP1 in invasion [14]. Disruption of the FP2A gene caused swollen food vacuoles due to accumulation of undegraded haemoglobin during trophozoite stage, which confirmed a major role of FP2A in haemoglobin degradation [12] [15]. "
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    ABSTRACT: Falcipain-3 (FP3) is an essential and drug target cysteine protease of the most lethal human malaria parasite Plasmodium falciparum. FP3 and its majority of homologs in malaria parasites prefer Leu at the P2 position in substrates and inhibitors, whereas its major host homolog cathepsin L prefers Phe. However, FP3 is much less active on peptide substrates and has negligible activity against a P2 Arg-containing substrate (Z-RR-AMC) compared to its paralog falcipain-2A (FP2A). To identify the specificity determinants, the S2/3 pocket residues of FP3 were substituted with the corresponding residues in FP2 or cathepsin L, and the wild type and mutant proteases were assessed for hydrolysis of peptide and protein substrates. Our results indicate that the S2 pocket residues I94 and P181of FP3 are chiefly responsible for its P2 Leu preference and negligible activity for Z-RR-AMC, respectively. E243 in FP3 and the corresponding residue D234 in FP2 have a key role in Z-RR-AMC hydrolysing activity, possibly through stabilization of side chain interactions, as their substitution with Ala abolished the activity. Several FP3 mutants, which retained P2 Leu preference and showed similar or more activity than wild type FP3 on peptide substrates, degraded haemoglobin less efficiently than wild type FP3, suggesting that multiple residues contribute to haemoglobinase activity. Furthermore, P181 and E243 appear to contribute to the optimum activity of FP3 in the food vacuole milieu (≈pH 5.5). The identification of residues determining specificity of FP3 could aid in developing specific inhibitors of FP3 and its homologs in malaria parasites.
    No preview · Article · Oct 2015 · Molecular and Biochemical Parasitology
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    • "They found that in the schizont stage where the parasite invasion occurs, only one protein (Falcipain 1) showed proteolytic activity. It was later utilized in enzymatic screening of a compound library that led to the discovery of YA29-Eps, a potent blocker of the parasite invasion (Greenbaum et al. 2002). "
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    ABSTRACT: Drug discovery and development is vital to the well-being of mankind and sustainability of the pharmaceutical industry. Using chemical biology approaches to discover drug leads has become a widely accepted path partially because of the completion of the Human Genome Project. Chemical biology mainly solves biological problems through searching previously unknown targets for pharmacologically active small molecules or finding ligands for well-defined drug targets. It is a powerful tool to study how these small molecules interact with their respective targets, as well as their roles in signal transduction, molecular recognition and cell functions. There have been an increasing number of new therapeutic targets being identified and subsequently validated as a result of advances in functional genomics, which in turn led to the discovery of numerous active small molecules via a variety of high-throughput screening initiatives. In this review, we highlight some applications of chemical biology in the context of drug discovery.
    Full-text · Article · Aug 2015 · Archives of Pharmacal Research
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