Ex vivo maturation of the malaria parasite egress protease SERA6 aids pathway dissection and inhibitor development

Ex vivo maturation of the malaria parasite egress protease SERA6 aids pathway dissection and inhibitor development | bioRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results Ex vivo maturation of the malaria parasite egress protease SERA6 aids pathway dissection and inhibitor development Chrislaine Withers-Martinez , Zahie Taha , Christine R Collins , Fiona Hackett , Michele SY Tan , Christelle Soudy , Dhira Joshi , Joanna Redmond , Benedict Davies , Sarah Maslen , Mark Skehel , Roger George , Svend Kjaer , View ORCID Profile Michael J Blackman doi: https://doi.org/10.64898/2026.01.29.702321 Chrislaine Withers-Martinez 1 Malaria Biochemistry Laboratory, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: chrislaine.withers-martinez{at}crick.ac.uk mike.blackman{at}crick.ac.uk Zahie Taha 1 Malaria Biochemistry Laboratory, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Christine R Collins 1 Malaria Biochemistry Laboratory, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Fiona Hackett 1 Malaria Biochemistry Laboratory, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michele SY Tan 1 Malaria Biochemistry Laboratory, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Christelle Soudy 2 Chemical Biology Science Technology Platform, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dhira Joshi 2 Chemical Biology Science Technology Platform, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joanna Redmond 2 Chemical Biology Science Technology Platform, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Benedict Davies 1 Malaria Biochemistry Laboratory, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sarah Maslen 3 Proteomics Science Technology Platform, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mark Skehel 3 Proteomics Science Technology Platform, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Roger George 4 Structural Biology Science Technology Platform, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Svend Kjaer 4 Structural Biology Science Technology Platform, The Francis Crick Institute , London NW1 1AT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael J Blackman 1 Malaria Biochemistry Laboratory, The Francis Crick Institute , London NW1 1AT, UK 5 Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine , London WC1E 7HT, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Michael J Blackman For correspondence: chrislaine.withers-martinez{at}crick.ac.uk mike.blackman{at}crick.ac.uk Abstract Full Text Info/History Metrics Supplementary material Preview PDF Abstract 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 and to show that these 3 components are sufficient for SERA6 maturation. 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 lead inhibitory compound efficiently blocks egress of asexual blood stage parasites, confirming SERA6 as a new potential antimalarial drug target. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared Cancer Research UK, https://ror.org/054225q67 , FC001043 Medical Research Council, https://ror.org/03x94j517 , FC001043 Wellcome Trust, https://ror.org/029chgv08 , FC001043 The Francis Crick Institute, https://ror.org/04tnbqb63 , P2019-0015 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted January 29, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. 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Share Ex vivo maturation of the malaria parasite egress protease SERA6 aids pathway dissection and inhibitor development Chrislaine Withers-Martinez , Zahie Taha , Christine R Collins , Fiona Hackett , Michele SY Tan , Christelle Soudy , Dhira Joshi , Joanna Redmond , Benedict Davies , Sarah Maslen , Mark Skehel , Roger George , Svend Kjaer , Michael J Blackman bioRxiv 2026.01.29.702321; doi: https://doi.org/10.64898/2026.01.29.702321 Share This Article: Copy Citation Tools Ex vivo maturation of the malaria parasite egress protease SERA6 aids pathway dissection and inhibitor development Chrislaine Withers-Martinez , Zahie Taha , Christine R Collins , Fiona Hackett , Michele SY Tan , Christelle Soudy , Dhira Joshi , Joanna Redmond , Benedict Davies , Sarah Maslen , Mark Skehel , Roger George , Svend Kjaer , Michael J Blackman bioRxiv 2026.01.29.702321; doi: https://doi.org/10.64898/2026.01.29.702321 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (8164) Biochemistry (19027) Bioengineering (15171) Bioinformatics (45808) Biophysics (22958) Cancer Biology (20248) Cell Biology (27495) Clinical Trials (138) Developmental Biology (14233) Ecology (21529) Epidemiology (2067) Evolutionary Biology (25940) Genetics (16436) Genomics (23979) Immunology (19176) Microbiology (43488) Molecular Biology (18483) Neuroscience (95839) Paleontology (717) Pathology (3064) Pharmacology and Toxicology (5253) Physiology (8339) Plant Biology (16378) Scientific Communication and Education (2123) Synthetic Biology (4675) Systems Biology (10451) Zoology (2436)

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