title: Proteases in Mosquito Borne Diseases: New Avenues in Drug Development.
abstract: Mosquito borne diseases continue to propagate and cause millions of deaths annually. They are caused either by protozoan parasites such as Plasmodium, Toxoplasma or by flaviviruses including Dengue and Zika. Among the proteome of such parasitic organisms, proteases play essential roles in events such as host invasion, hemoglobin hydrolysis, replication and immune evasion. Plasmepsin V (PMV), an endoplasmic reticulum resident aspartic protease of Plasmodium spp., is involved in the export of ~400 proteins containing the conserved Plasmodium Export Element motif (PEXEL). Interactions and cleavage of PEXEL proteins by PM V is necessary for export to and across the parasitophorous vacuole membrane. Protease System: Similarly in flaviviruses, a two-component protease system consisting of nonstructural proteins, NS2B and NS3, interacts with other non-structural proteins and plays a major role in viral replication, polyprotein cleavage and virion particle assembly. Thus, proteases involved in indispensable roles in pathogen machinery can be considered as attractive drug targets. Inhibitors against proteases are being used in clinical trials for other communicable and non-communicable diseases. Currently, hydroxyethylamine based inhibitors targeting the catalytic site of PM V with picomolar inhibitory concentrations have been tested in vitro.
  
  
  
  For recently characterized disease such as Zika, no known treatments exist while compound such as Policresulen has high affinity for Dengue NS2B/NS3 complex. Understanding proteases structure-function relationship and protease-inhibitor interactions can provide new insights for novel chemotherapeutic strategies.
authors.affiliation: National Institute of Malaria Research, Dwarka Sector - 8, New Delhi - 110077, India|Department of Biotechnology, Kumaun University, Nainital, Uttarakhand – 263001, India
authors.forename: A
authors.initials: A
authors.lastname: Pant
authors.affiliation: National Institute of Malaria Research, Dwarka Sector - 8, New Delhi - 110077, India|Institute of Science, Nirma University, SG Highway, Ahmedabad, Gujarat - 382481, India
authors.forename: R
authors.initials: R
authors.lastname: Pasupureddy
authors.affiliation: Department of Biotechnology, Kumaun University, Nainital, Uttarakhand – 263001, India
authors.forename: V
authors.initials: V
authors.lastname: Pande
authors.affiliation: Institute of Science, Nirma University, SG Highway, Ahmedabad, Gujarat - 382481, India
authors.forename: S
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: National Institute of Malaria Research, Dwarka Sector - 8, New Delhi - 110077, India
authors.forename: R
authors.initials: R
authors.lastname: Dixit
authors.affiliation: Department of Biochemistry, National Institute for Research in Environmental Health, Bhopal, MP - 462001, India
authors.forename: K C
authors.initials: KC
authors.lastname: Pandey
mesh_terms: D000818:Animals; D003716:Dengue Virus / Q000187:drug effects / Q000201:enzymology; D015195:Drug Design; D000072138:Mosquito Vectors; D010447:Peptide Hydrolases / Q000378:metabolism*; D010961:Plasmodium / Q000187:drug effects / Q000201:enzymology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000071244:Zika Virus / Q000187:drug effects / Q000201:enzymology
chemical_list: D011480:Protease Inhibitors; D010447:Peptide Hydrolases
keywords: Dengue; Malaria; NS2B-NS3; Plasmepsin V; Protease; Protease Inhibition; Protein Interaction; Zika