%0 Journal Article %A Arpita Banerjee %A Ruben Abagyan %T Cysteine proteases of hookworm Necator Americanus as virulence factors and implications for future drug design: A bioinformatics-based study %D 2017 %R 10.1101/116921 %J bioRxiv %P 116921 %X Human hookworm Necator Americanus causes iron deficiency anemia, as the parasite ingests blood from the gastrointestinal tract of its human host. The virulence factors of this blood feeding nematode have not been researched extensively. This bioinformatics based study focuses on eight of the cathepsin B like cysteine proteases (CPs) of the worm, which could have immense pathogenic potential. The role of the individual CPs remain vaguely determined except for CP3 which has been shown to act as globinase in the hemoglobin degradation pathway. In this study, the cysteine proteases were subjected to predictive molecular characterizations viz: probability of extracellular secretion to the interface between pathogen and host, ability for hemoglobin degradation, and/or interaction with host plasma proteins. CP1- CP6, which harbored the active site cysteine were also observed to have N terminal signal peptide for extracellular localization, and were relevantly predicted to be secretory. Amongst these, CP2 and CP3 showed the presence of hemoglobinase motif derived in this study that could be a prerequisite for globin or hemoglobin degradation. Active site correlation of the secretory CPs with human pKal that cleaves high molecular weight kininogen (HMWK) to prevent platelet activation is suggestive of the involvement of hookworm CPs in preventing the formation of blood clots via this pathway. NA CP1, CP2, CP3, CP5 and CP6 were predicted to bind heparin, which is the glycosaminoglycan molecule that has been demonstrated to aid the functionality of other cysteine proteases like human cathepsin B and cruzain. Heparin docked onto the NA CPs at the C terminal domain, away from the active site, similar to what has been shown for heparin binding to cathepsin B, and cruzain that cleaves HMWK. These observations therefore lead to the hypothesis that the functions of the hookworm CPs, which would probably include blood clot prevention, could be assisted by heparin. This study underscores the potential of synthetic heparin analogs as molecular treatment for hookworm infection, which could have implications for future drug design. %U https://www.biorxiv.org/content/biorxiv/early/2017/03/24/116921.full.pdf