Malaria afflicts about half of the world population causing over 400,000 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 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 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 ones that demonstrate curative and prophylactic activities. 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 and targeting them for therapy . 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.
- Collins JE, Lee JW, Bohmer MJ, Welden JD, Arshadi AK, Du L, Cichewicz RH, Chakrabarti D. (2021) Cyclic tetrapeptide HDAC inhibitors with improved Plasmodium falciparum selectivity and killing profile. ACS Infect Dis. 7:2889-2903. doi: 10.1021/acsinfecdis.1c00341. PMID: 34491031
- Norwood VM 4th, Murillo-Solano, Goertzen MG 2nd, Brummel BR, Perry DL, Rocca JR, Chakrabarti D, Huigens RW 3rd (2021) Ring distortion of vincamine leads to the identification of re-engineered antiplasmodial agents. ACS Omega 6:20455-20470. doi:10.1021/acsomega.1c02480. PMID:34395993. (co-corresponding author)
- 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 19:179 doi:10.3390/md19040179. PMID 33805935 (journal cover)
- Lee JW, Collins JE, Wendt KL, Chakrabarti D, Cichewicz RH (2021) Leveraging peptaibol biosynthetic promiscuity for next-generation antiplasmodial therapeutics. J Nat Prod 84:503-517. Doi: 10.1021/acs.jmatprod.0c01370. PMID: 33565879 (co-corresponding author)
- Huang G, Murillo-Solano CM, 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. PMID: 33045660 (co-corresponding author)
- 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 63:11756-11785. doi: 10.1021/acs.jmedchem.0c00858 PMID: 32959656 (co-corresponding author)
- Keshavarzi A, Salem, M, Collins, J, Yuan JS, Chakrabarti D (2020) DeepMalaria: artificial intelligence driven discovery of potent antiplasmodials. Front Pharmacol 10:1526. doi: 10.3389/fphar. 2019.01526. PMID: 32009951
- Paciaroni NG, Perry DL 2nd, Norwood VM 4th, Murillo-Solano C, Collins, J, Tenneti S, Chakrabarti D, Huigens RW 3rd (2020) Re-engioneering of yohimbine’s biological activity through ring distortion identification and structure-activity relationships of anew class of antiplasmodial agents. ACS Infect Dis 6:159-167. doi: 10.1021/acsinfecdis.9b00380. PMID: 31913597 (Journal cover, co-corresponding author)
- Huang G, Solano CM, 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. doi: 10.1016/j.tetlet.2019.05.054. PMID: 31802783
- McCarthy PJ, Roberts BF, Carbonell A, Roberts J, Wright AE, Chakrabarti D (2019) Marine microbiome as a source of antimalarials. Trop Med Infect Dis 4:103. Doi: 10.3390/tropicalmed4030103. PMID: 31337089
- Perry DL, Roberts BF, Debevec G, Michaels HA, Chakrabarti D, Nefzi A (2019) Identification of bis-cyclic guanidines as antiplasmodial compounds from positional scanning mixture-based libraries. Molecules 24:1100. Doi: 10.3390/molecules24061100. PMID: 30897744.
- Pease BN, Huttlin, EL, Jedrychowski MP. Dorin-Semblat D, Sebastini D, Segarra DT, Roberts BF, Chakrabarti R, Doerig C, Gygi SP, Chakrabarti D. (2018) Characterization of Plasmodium falciparum atypical kinase PfPK7-dependent phosphoproteome. J Proteome Res 17: 2112-2123. Doi: 10.1021/acs.jproteome.8b00062.
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