Ex vivo maturation of the malaria parasite egress protease SERA6 aids pathway dissection and inhibitor development
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Chrislaine Withers-Martinez Zahie Taha Christine R Collins Fiona Hackett Ser Ying Tan Christelle Soudy Dhira Joshi Joanna Redmond Benedict Davies Sarah Maslen Mark Skehel Roger George Svend Kjaer Michael BlackmanAbstract
Release (egress) of malaria parasites from host red blood cells (RBC) is a protease-dependent process involving breakdown of the RBC cytoskeleton by a parasite cysteine protease-like protein called SERA6. In the penultimate step of the egress cascade, SERA6 undergoes autoproteolytic maturation triggered upon cleavage by a serine protease called SUB1 and requiring interactions between SERA6 and fragments of another parasite protein called MSA180. Egress can be blocked by treatment of intraerythrocytic parasites with small molecules that prevent the autocatalytic SERA6 maturation step, suggesting that SERA6 is a druggable target. Here we describe the development of a cell-free in vitro system that recapitulates SERA6 maturation. We use the assay to confirm the strict requirement for MSA180 in SERA6 maturation by SUB1. Using a synthetic peptide substrate based on a predicted autocatalytic cleavage site we demonstrate that the fully mature SERA6 is an active proteolytic enzyme and we validate improved small molecule inhibitors of SERA6. Our best inhibitory compound efficiently blocks egress of asexual blood-stage parasites, confirming SERA6 as a new potential antimalarial drug target.
Journal details
Journal
Frontiers in Parasitology
Volume
5
Pages
1823181
Available online
Publication date
Full text links
Publisher website (DOI)
10.3389/fpara.2026.1823181
Figshare
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Europe PubMed Central
42662414
Pubmed
42662414
Publishing history
The publication was previously a preprint.
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