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.
- Wright AE, Collins JE, Roberts B, Roberts JC, Winder PL, Reed JK, Diaz MC, Pomponi SA,Chakrabarti D. (2021) Antiplasmodial compounds from deep-water marine invertebrates. Mar. Drugs 19(4):179. doi: 10.3390/md19040179.
- Lee, J.W., Collins, J. E., Wendt, K.L., Chakrabarti, D., Cichewicz, R.H. (2021) Leveraging peptaibol biosynthetic promiscuity for next-generation antiplasmodial therapeutics. (co-corresponding author) J. Nat. Prod. Doi: 10.1021/acs.jnatprod.0c01370.
- Huang, G., Murillo-Solano, M., Melendez, J., Yu-Alfonzo, S., Boonhok, R., Min, H., Miao, J., Chakrabarti, D., Yuan, Y. (2021) Discovery of fast-acting dual-stage antimalarial agents by profiling pyridylvinylquinoline chemical space via copper catalyzed azide-alkyne cycloadditions. (Co-corresponding author) European J. Med. Chem. 209:112889. doi: 10.11016/j.ejmech.2020.112889
- Huang, G., Murillo-Solano, C., Melendez, J., Shaw, J., Collins, J., Bank, R., Boonhok, R., Min, H., Miao, J., Chakrabarti, D., Yuan, Y. (2020) Synthesis, structure-activity relationship and antimalarial efficacy of 6-chloro-2-arylvinylquinolines. J. Med. Chem. doi: 10.1021/acs.jmedchem.0c00858 (Co-corresponding author)
- Paciaroni, N.G., Perry, D.L., Norwood, V. M. Murillo-Solano, C., Collins, J., Tewnneti, S., Chakrabarti, D., Huigens, R. W. (2020) Re-engineering of yohimbine’s biological activity through ring distortion identification and structure-activity relationships of a new class of antiplasmodial agents. 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, G., 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.
- 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. 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.
- 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., Killday, K. B., Chakrabarti, D., Guzman, E., Harmody, D., McCarthy, P. J., Pitts, T., Pomponi, S., Reed, J. K., Roberts, B. F., Felix, C. F., Rohde, K. H. (2017) Dragmacidin G, a bioactive bis-indole alkaloid from deep-water sponge of the genus Spongosorites. Marine Drugs 15, 16.
- 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.