Malaria afflicts about half of the world population causing over 500,000 deaths each year. In addition to contributing significantly towards overall childhood mortality in the poorest nations, the disease is estimated to cause considerable reductions in the economic growth of countries that bear a heavy malaria burden. The situation is made worse because the widespread prevalence of drug resistant parasites is rendering the limited number of available drugs less and less effective for clinical use. Therefore, there is a pressing need for novel therapeutic options to treat multidrug resistant malaria. It is also important to understand the molecular mechanism of parasite growth and differentiation so that novel therapeutic targets can be identified.
A major focus of research in my laboratory is to identify next generation of antimalarial compounds from unique areas of medicinally relevant chemical space. To pursue this goal we are engaged in screening focused libraries of natural product-based synthetic compounds as well as natural product extracts from under explored marine biodiversity and fungi. Our research has discovered many novel scaffolds with potent and selective antiplasmodial activities with cellular action distinct from current antimalarials, including one that cures malaria in the rodent model. Another aspect of research in my laboratory focuses on understanding molecular mechanisms of the intraerythrocytic life cycle of the malaria parasite, Plasmodium falciparum. Specifically, we are engaged in defining precise physiological roles of Plasmodium protein kinases that are key regulators of its complex developmental stages through identification of their substrates. We recently performed isobaric tag-based quantitative proteomics and phosphoproteomics analyses of three developmental stages in the Plasmodium asexual cycle. Our system-wide comprehensive analysis is a major step towards elucidation of kinase-substrate pairs operative in various signaling networks in the parasite. This rich dataset will be useful in defining and targeting the parasite’s signaling network. Many of the unique features of parasite protein kinases can potentially be exploited to design new generation of malaria therapeutics.
- Paciaroni, N.G., Perry, D.L., Norwood, V. M. Murillo-Solano, C., Collins, J., Tewnneti, S., Chakrabarti, D., Huigens, R. W. (2020) ACS Infect. Dis. 6, 159-167 doi: 10.1021/acsinfecdis.9b00380. (Co-Corresponding author, Journal Cover)
- Arshadi, A.K., Salem, M., Collins, J., Yuan, J. S., Chakrabarti D. (2020) DeepMalaria: Artificial intelligence driven discovery of potent antimalarials. Front. Pharmacology. doi.org/10.3389/fpharm.2019.01526
- McCarthy, P. J., Roberts, B. F., Carbonell, A., Roberts, J., Wright, A. E., Chakrabarti, D. (2019) Marine microbiome as a source of antimalarials. Trop Med Infect Dis. 4, 103; doi:10.3390/tropicalmed4030103.
- Huang, H., Solano, C. M., Su, Y., Ezzat, N., Matsui, S., Huang, L., Chakrabarti, D.*, Yuan, Y.* (2019) Microwave-assisted rapid synthesis of 2-vinylquinolines and evaluation of their antimalarial activity. Tetrahedron Lett. 60, 1736-1740. (* corresponding authors)
- Perry, D.L., Jr., Roberts, B.F. Debevec, G., Michaels, H.A. Chakrabarti, D, Nefzi, A. (2019) Identification of Bis-Cyclic Guanidines as Antiplasmodial Compounds from Scanning Mixture-based Libraries. Molecules. Mar 20;24(6). pii: E1100.
- Pease, B., Huttlin, E., Jedrychowski, M.P., Dorin-Semblat, D., Sebastiani, Segarra, D.T., Roberts, B.F., Chakrabarti, R., Doerig, C., Gygi, S., Chakrabarti, D. (2018) Characterization of Plasmodium falciparum atypical kinase PfPK7-dependent phosphoproteome. J. Proteome Res. 17, 2112-2123.
- Pease, B.N., Huttlin, E. L., Roberts, B.F., Jedrychowski, M.P., Dorin-Semblat, D., Sebastiani, D. M., Segarra, D.T., Chakrabarti, R., Doerig, C., Gygi, S.P., Chakrabarti, D. (2018) Characterization of Plasmodium falciparum Atypical Kinase PfPK7-dependent Phosphoproteome. J Proteome Res. 2018 Apr 20. doi: 10.1021/acs.jproteome.8b00062. [Epub ahead of print]
- Roberts, B., Zheng, Y., Cleaveleand, J., Ayong, L., Yuan, Y., Chakrabarti, D. (2017) 4-Nitro Styrylquinoline is an Antimalarial Inhibiting Multiple Stages of Plasmodium Asexual Life Cycle. Int. J. Parasitol. Drugs & Drug Resist. 7, 120-129.
- Wright, A.E., Kilday, K.B., Chakrabarti, D., Guzman, E.A., Harmody, D., McCarthy, P.J., Pitts, T., Pomponi, S.A., Reed, J.K., Roberts, B.F., Rodrigues, F.C., Rohde, K. H. (2017) Dragmacidin G, a bioactive bisindole alkaloid from a deep-water sponge of the genus Sporongosoites. 15, 16. Mar. Drugs. PMID: 28085024
- Roberts, B.F., Iyamu, I.D., Lee, S., Lee, E., Ayong, L., Kyle, D.E., Yuan, Y., Manetsch, R., Chakrabarti, D. (2016) Spirocyclic chromanes exhibit antiplasmodial activities and inhibit all intraerythrocytic life cycle stages. Int. J. Parasitol. Drugs Drug Resist. 6, 85-92.
- Chakrabarti, D. and Wright, A. (2015) Anti-malarial compounds from marine natural compounds. US Patent: 9,181,251 B2. Nov 10, 2015.
- Arora, S., Mauser, J., Chakrabarti, D., Schulte, A. (2015) Spatially resolved micro-absorption spectroscopy with a broadband source and confocal detection. Optics Communication, 355, 533-537.
- Koyama, F.C., Azevedo, M.F., Budu, A., Chakrabarti, D., Garcia, C.R. (2014) Melatonin-induced upregulation of gene expression related to ubiquitin/proteasome system in human malaria parasite Plasmodium falciparum. Int. J. Mol. Sci. 15, 22320-30.
- Pease, B., Huttlin, E., Jedrychowski, M.P., Talevich, E., Harmon, J., Dillman, T., Kannan, N., Doerig, C., Chakrabarti, R., Gygi, S., Chakrabarti, D. (2013) Global analysis of protein expression and phosphorylation of three stages of Plasmodium falciparum intraerythrocytic development. J. Proteome. Res. 12, 4028-45.
- Alvarado, S. Roberts, BF, Wright, A.E., Chakrabarti, D. (2013) The bis(indolyl)imidazole alkaloid nortopsentin A exhibits antiplasmodial activity. Antimicrob Agents Chemother 57, 2362-64.
- Dorin-Semblat, D., Carvalho, T. G., Nivez, M-P.,Goldring, D., Chakrabarti, D., Dhar, S., Goldberg, D., Tilley, L., Doerig, C. (2013) An atypical cyclin-dependent kinase controls Plasmodium falciparum proliferation rate. Kinome 1, 4-16.
- Koyama, F.C., Ribiero, R.Y., Garcia, J.L. Chakrabarti, D., and Garcia, C.R. (2012) Ubiquitin proteasome system and the atypical kinase PfPK7 are involved in melatonin signaling in Plasmodium falciparum . J. Pineal Res. 53, 147-53.
- Dorin-Semblat, D., Goldring, D., Patterson, S., Quashie, N., Reininger, L., Schmitt, S., Meijer, L., Chakrabarti, D., and Doerig, C. (2011) Plasmodium falciparum NIMA-related kinase Pfnek-1: sex-specificity, essentiality for the erythrocytic asexual cycle. Microbiology 157, 2785-94.
- Ayong, L., Da Silva, T., Mauser, J., Allen, C.A., Chakrabarti, D. (2011) Evidence for prenylation-dependent targeting of a Ykt6 SNARE in Plasmodium falciparum. Mol. Biochem. Parasitol. 175, 162-8.
- Halbert, J., Ayong, L., Equinet, L., Le Roch, K., Hardy, M., Goldring, D., Chakrabarti, D., Reininger, L., Doerig, C. (2010) A Plasmodium falciparum transcriptional cyclin-dependent kinase-related kinase with a crucial role in parasite proliferation associates with histone deacytylase activity. Eukaryot. Cell 9, 952-9.
- Davoodi-Semiromi A., Schreiber, M., Nalapalli, S., Verma, D., Singh, N. D, Banks, R. K., Chakrabarti, D., Daniell, H. (2010) Chloroplast-derived vaccine antigens confer dual immunity against cholera and malaria by oral and injectable delivery. Plant Biotechnol. J., 8, 223-48.
- Ayong, L., Raghavan, A., Schneider, T.G., Taraschi, T. F., Fidock, D. A., Chakrabarti, D. (2009). The longin domain regulates the steady state dynamics of Sec 22 in Plasmodium falciparum. Eukaryot. Cell, 8, 1330-40.
- Koyama, F.C., Chakrabarti, D., Garcia C. R. (2009) Molecular Machinery of signal transduction and cell cycle regulation in Plasmodium. Mol. Biochem. Parasitol. 165, 1-7.
- Chakrabarti, D. (2009). A methods-based biotechnology course for undergraduates. Biochem. Mol. Biol. Educ. 37, 227-31.
- Chakrabarti, R., Chakrabarti, D. (2009) Chemotherapeutics of neglected waterbourne parasites: current status and future perspectives. Mol. Cell. Pharmacol. 1, 98-102.