Genetic and structural characterization of PvSERA4: potential implication as therapeutic target for Plasmodium vivax malaria

Abstract

Plasmodium vivax malaria is geographically the most widely distributed and prevalent form of human malaria. The development of drug resistance by the parasite to existing drugs necessitates higher focus to explore and identify new drug targets. Plasmodial proteases have key roles in parasite biology and are involved in nutritional uptake, egress from infected reticulocytes, and invasion of the new target erythrocytes. Serine repeat antigens (SERA) of Plasmodium are parasite proteases that remain attractive drug targets and are important vaccine candidates due to their high expression profiles in the blood stages. SERA proteins have a unique putative papain-like cysteine protease motif that has either serine or cysteine in its active site. In P. vivax, PvSERA4 is the highest transcribed member of this multigene family. In this study, we have investigated the genetic polymorphism of PvSERA4 central protease domain and deduced its 3D model by homology modeling and also performed MD simulations to acquire refined protein structure. Sequence analysis of protease domain of PvSERA4 from Indian field isolates reveals that the central domain is highly conserved. The high sequence conservation of the PvSERA4 enzyme domain coupled with its high expression raises the possibility of it having a critical role in parasite biology and hence, being a reliable target for new selective inhibitor-based antimalarial chemotherapeutics. The 3D model showed the presence of an unusual antiparallel Beta hairpin motif between catalytic residues similar to hemoglobin binding motif of Plasmodial hemoglobinases. Our PvSERA4 model will aid in designing structure-based inhibitors against this enzyme.

Keywords:

• Plasmodium vivax (PV)
• serine repeat antigen (SERA)
• protease domain
• homology modeling
• genetic polymorphism

Acknowledgments

This study was supported by the Department of Science and Technology (DST), New Delhi. India [SR/FT/LS-061]. We would also like to thank UGC-CSIR, New Delhi, India for funding the research scholar. We thank, Dr Ramakrishna Vadrevu for his constructive suggestions and useful discussions. We thank Ms Madhu Poornima for her technical support and proofreading the article.