title: Small molecule targeting malaria merozoite surface protein-1 (MSP-1) prevents host invasion of divergent plasmodial species.
abstract: Malaria causes nearly 1 million deaths annually. Recent emergence of multidrug resistance highlights the need to develop novel therapeutic interventions against human malaria. Given the involvement of sugar binding plasmodial proteins in host invasion, we set out to identify such proteins as targets of small glycans. Combining multidisciplinary approaches, we report the discovery of a small molecule inhibitor, NIC, capable of inhibiting host invasion through interacting with a major invasion-related protein, merozoite surface protein-1 (MSP-1). This interaction was validated through computational, biochemical, and biophysical tools. Importantly, treatment with NIC prevented host invasion by Plasmodium falciparum and Plasmodium vivax--major causative organisms of human malaria. MSP-1, an indispensable antigen critical for invasion and suitably localized in abundance on the merozoite surface represents an ideal target for antimalarial development. The ability to target merozoite invasion proteins with specific small inhibitors opens up a new avenue to target this important pathogen.
authors.affiliation: Interdisciplinary Research Group of Infectious Diseases, Singapore MIT Alliance for Research and Technology Centre (SMART) Singapore University of Technology and Design, 20 Dover Drive.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chandramohanadas
authors.affiliation: Interdisciplinary Research Group of Infectious Diseases, Singapore MIT Alliance for Research and Technology Centre (SMART).
authors.lastname: Basappa
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore and.
authors.forename: Bruce
authors.initials: B
authors.lastname: Russell
authors.affiliation: Interdisciplinary Research Group of Infectious Diseases, Singapore MIT Alliance for Research and Technology Centre (SMART).
authors.forename: Kingsley
authors.initials: K
authors.lastname: Liew
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Yin Hoe
authors.initials: YH
authors.lastname: Yau
authors.affiliation: Interdisciplinary Research Group of Infectious Diseases, Singapore MIT Alliance for Research and Technology Centre (SMART).
authors.forename: Alvin
authors.initials: A
authors.lastname: Chong
authors.affiliation: Interdisciplinary Research Group of Infectious Diseases, Singapore MIT Alliance for Research and Technology Centre (SMART).
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Karthigayan
authors.initials: K
authors.lastname: Gunalan
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Rahul
authors.initials: R
authors.lastname: Raman
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR).
authors.forename: Laurent
authors.initials: L
authors.lastname: Renia
authors.affiliation: Shoklo Malaria Research Unit, Mae Sot, Thailand Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, United Kingdom.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Susana Geifman
authors.initials: SG
authors.lastname: Shochat
authors.affiliation: Interdisciplinary Research Group of Infectious Diseases, Singapore MIT Alliance for Research and Technology Centre (SMART) Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge;
authors.forename: Ming
authors.initials: M
authors.lastname: Dao
authors.affiliation: Interdisciplinary Research Group of Infectious Diseases, Singapore MIT Alliance for Research and Technology Centre (SMART) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Ram
authors.initials: R
authors.lastname: Sasisekharan
authors.affiliation: Department of Biomedical Engineering and Department of Materials Science and Engineering, Carnegie Mellon University, Pittsburgh.
authors.forename: Subra
authors.initials: S
authors.lastname: Suresh
authors.affiliation: Interdisciplinary Research Group of Infectious Diseases, Singapore MIT Alliance for Research and Technology Centre (SMART) School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Peter
authors.initials: P
authors.lastname: Preiser
mesh_terms: D000962:Antimalarials / Q000302:isolation & purification* / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects*; D006801:Humans; D020066:Merozoite Surface Protein 1 / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000187:drug effects*; D010966:Plasmodium vivax / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D020066:Merozoite Surface Protein 1
keywords: Plasmodium falciparum; Plasmodium vivax; chemical biology; glycan mimetic small molecules; host invasion; malaria; mass spectrometry; merozoite surface proteins; red blood cell