Inhibitors of Plasmepsin V as Novel Anti-Malarial Agents
Project Summary and Proposal
Each year there are approximately 350-500 million cases of malaria, killing between one and three million people, the majority of whom are young children in sub-Saharan Africa, where ninety percent of malaria-related deaths occur. Although there are a number of drugs used to treat malaria, resistance to these drugs is becoming more widespread. Thus, therapies targeting novel modes of action are greatly needed. One promising new antimalarial target is the Plasmodium specific aspartyl protease, Plasmepsin V (PMV), recently discovered to be the key gate keeping protease responsible for the cleavage and translocation of several hundred PEXEL-containing proteins destined for export into the host erythrocyte. PMV and many of these downstream PEXEL-containing export proteins are essential for the survival of the parasite. The aim of this project is to identify potent inhibitors of PMV and demonstrate their therapeutic value for the treatment of malaria.
GIBH in partnership with the Center for World Health & Medicine (CWHM) at Saint Louis University has established a powerful collaboration. This collaboration has the expertise and resources necessary to successfully drive this project to validate the target pharmacologically and ultimately identify a clinical candidate for malaria.
Background and Rationale
Malaria is a devastating mosquito-borne infectious disease caused by a parasite of the genus Plasmodium. It is widespread in tropical and subtropical regions, including Central and South America, Asia, and Africa. Each year there are approximately 350-500 million cases of malaria, killing between one and three million people, the majority of whom are young children in sub-Saharan Africa, where ninety percent of malaria-related deaths occur. Malaria is commonly associated with poverty, but it is also a cause of poverty and a major hindrance to economic development. Although there are a number of drugs used to treat malaria, resistance to these drugs is becoming more widespread. Thus, therapies targeting novel modes of action are greatly needed. The Center for World Health & Medicine (CWHM), in collaboration with academic researchers, will look to exploit newly discovered mechanisms believed to be critical for the parasite Plasmodium falciparum survival by testing specific classes of drugs that may block these mechanisms. This offers the potential for development of new therapies to treat this widespread tropical disease.
The life cycle of P. falciparum in the human host involves infection of erythrocytes by merozoites which replicate and infect additional red blood cells, resulting in massive parasite multiplication (asexual blood stage replication). After invasion of the erythrocyte, the parasite exports hundreds of effector proteins across the parasitophorous vacuole membrane (PVM) into the erythrocytic cytoplasm. These proteins are necessary for remodeling the host erythrocyte into an environment suitable for parasite multiplication and are essential for survival of the parasite. Export of these effector proteins is dependent on a conserved N-terminal export sequence (termed PEXEL, RxLxE/Q/D). Plasmepsin V (PMV) has recently been identified by two independent laboratories as the aspartyl protease responsible for cleavage of the PEXEL sequence revealing the xE/Q/D export signal. PMV has been shown to be necessary for P. falciparum viability and represents a very promising new anti-malarial target, given its central role in the export of hundreds of proteins exported for erythrocyte remodeling. The objective of this project is to identify inhibitors of PMV and demonstrate their therapeutic value in the treatment of malaria.
Partner
The Center for World Health & Medicine, Saint Louis University (www.cwhm.org). The CWHM is a non-profit group whose expertise is the translation of basic science into the discovery and development of novel drugs for rare and neglected diseases. The CWHM consists of a highly skilled and successful team of former Pfizer drug discovery scientists. The scientists on this team have expertise at high throughput protease assay development, drug design and medicinal chemistry, in vivo pharmacology and pharmacokinetics, and preclinical development.
Project Strategy
Principal Objective. Develop a safe, effective, and affordable inhibitor of Plasmepsin V as a human therapeutic treatment for malaria.
Approach. HIV-1 aspartyl protease inhibitors lopinavir, ritonavir, saquinavir, and nelfinavir have been demonstrated to be weak inhibitors of PMV (~15-100 µM). This is not surprising, given the distant homology of PMV to other aspartyl proteases such as β-secretase and similarities between the PEXEL sequence in substrates for PMV and protein substrates of HIV-1 aspartyl protease. However, with molecular weights exceeding 700 and weak potencies, these HIV protease inhibitors are not good starting points for optimization towards an anti-malarial drug. Our approach to identifying a more suitable starting point for optimization involves (1) screening collections of aspartyl protease inhibitors to be secured from commercial, literature, pharmaceutical donors, and our internal medicinal chemistry program, and (2) an internal medicinal chemistry program aimed at designing transition-state mimics based on literature compounds and the PEXEL sequence. Our medicinal chemistry program would then be aimed at generation of PMV SAR and optimization for PMV enzyme and cellular potency to provide proof-of-concept for PMV inhibitors as anti-malarial agents .
