Research Groups

Mammalian Biology: Malaria

Research Interests and Description

Staff Research Scientist: Asif Mohmmed

Group Leader: Virander Chauhan

Research Interests

Characterization of novel drug targets for Plasmodium falciparum; Antigen discovery, identification and characterization of novel P. falciparum proteins involved in red cell invasion; protein trafficking machinery in the malaria parasite.

Description of Research

Characterization of Plasmodium falciparum proteins as novel drug targets
We have been working on ATP dependent protease machineries in the parasite as novel drug targets and have identified the P. falciparum ClpQY protease system as potential drug target machinery in the parasite. The ClpQY system is the prokaryotic counterpart of eukaryotic 20S proteasome that plays important role in cell cycle regulation. We have characterized the PfClpQ protease and shown that it harbors threonine protease specific activity as well as chymotrypsin like and peptidyl glutamyl peptide hydrolase activities. By generating a transgenic parasite line expressing fusion protein of GFP and Arc-repressor gene, a known target of ClpQ protease in the prokaryotes, we confirmed the activity of the protease machinery in the parasite. We also ascertained the functional significance of the protease for survival of the parasite by silencing the PfClpQ gene using siRNAs. In collaboration with the Structural and Computational Biology group of ICGEB we are in silico screening libraries of small molecules to identify possible specific inhibitors against these proteases that may act as lead compounds to design drugs against malaria. We have carried out the molecular modeling of the interaction between PfClpQ and PfClpY subunits and identified the interface residues. These studies may form basis to design strategies to target this protease machinery to develop antimalarials.
Identification and characterization of Merozoite Surface/Apical Proteins: novel vaccine target antigens
To identify novel merozoite surface/apical organelle proteins that might be involved in merozoite attachment and its invasion in RBC, we in silico screened P. falciparum proteome database. Some of the hypothetical proteins that grouped in transcriptome analysis with 28 other P. falciparum antigens which have been previously associated with the process of merozoite invasion, were identified to study further. We carried out localization of these proteins in the parasite by a GFP targeting approach using an inducible expression system that directs strong, schizont-stage expression of the transgene. Using these strategies we have identified a novel asparagine rich merozoite protein that localizes in the apical ends of the secretory organelle rhoptries in the merozoites; and was named P. falciparum apical asparagines rich protein (PfAARP). Detailed studies with recombinant PfAARP expressed on the COS cell surfaces and in the E. coli expression system suggested its role in RBC binding during invasion of the merozoites into the host RBCs. Parasite growth inhibition assays using anti-PfAARP antibody also confirmed its role in the process of merozoite invasion. These results support PfAARP to be a novel vaccine/drug target candidate.
In addition, we have also identified and characterized a novel merozoite surface protein in P. falciparum that harbors a central Duffy binding-like (DBL) domain and a secreted polymorphic antigen associated with merozoites (SPAM) domain.
Protein trafficking machinery in the parasite
We are also involved in understanding the protein trafficking in the parasite and in the infected RBCs. We have recently studied the trafficking and processing of an important food vacuole protease, falcipain-2, using the GFP targeting approach. We are presently trying to identify and characterize novel parasite specific protein-transporters that may be developed as novel targets against the parasite.

Recent Publications

Gangwar, D., Kalita, M.K., Gupta, D., Chauhan, V.S., Mohmmed, A. 2009. A systematic classification of Plasmodium falciparum P-loop NTPases: structural and functional correlation. Malar J. 18, 69

Wickramarachchi, T., Cabrera, A.L., Sinha, D., Dhawan, S., Chandran, T., Devi, Y.S., Kono, M., Spielmann, T., Gilberger, T.W., Chauhan, V.S., Mohmmed, A. 2009 A novel Plasmodium falciparum erythrocyte binding protein associated with the merozoite surface, PfDBLMSP, Int J Parasitol. 39, 763-773

Subramaniam, S., Mohmmed, A, Gupta, D. 2008. Molecular modeling studies of the interaction between Plasmodium falciparum HslU and HslV subunits. J. Biomol. Struc. Dyn. 26, 473-479

Wickramarachchi, T., Devi, Y.S., Mohmmed, A., Chauhan, V.S. 2008. Identification and characterization of a novel Plasmodium falciparum merozoite apical protein involved in erythrocyte binding and invasion. PLoS ONE, 3, e1732

Genova-Kalou, P., Dundarova, D., Idakieva, K., Mohmmed, A., Dundarov, S., Argirova, R. 2008. Anti-herpes effect of hemocyanin derived from the mollusk Rapana thomasiana. Z. Naturforsch [C]. 63, 429-434