Abstract
SummaryArtemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets. In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addition, WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.
Highlights
Several hundred million infections and 430,000–618,700 deaths each year occur because of malaria: the most lethal disease is caused by Plasmodium falciparum with the major burden of mortality and morbidity in Africa (Weiss et al, 2019)
A drug regimen acting on novel targets at multiple life cycle stages would enhance its utility and longevity for malaria elimination, because there is a reduced likelihood of parasites with pre-existing resistance mutations being present in the population
In the antimalarial drug space, the essential P. falciparum aspartic proteases, plasmepsins IX and X (PMIX and PMX), are potential targets since inhibitors block parasite egress and invasion and prevent maturation of rhoptry and micronemal proteins required for this process (Nasamu et al, 2017; Pino et al, 2017)
Summary
Several hundred million infections and 430,000–618,700 deaths each year occur because of malaria: the most lethal disease is caused by Plasmodium falciparum with the major burden of mortality and morbidity in Africa (Weiss et al, 2019). A series of proteolytic events are essential for egress from and invasion of host cells by P. falciparum (Alaganan et al, 2017). The subtilisin-like protease subtilisin 1 (SUB1) plays a key role and is involved in remodeling the merozoite surface and egress from the host erythrocyte (Collins et al, 2017; Silmon de Monerri et al, 2011). SUB1 processes the serine-repeat antigens 5 and 6 (SERA5 or 6), that are involved in host cell egress (Collins et al, 2017; Thomas et al, 2018). The downstream events mediated by these subtilisins are well described, there remains an incomplete understanding of how they are activated
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.