Project Scientist, UCSD
Skaggs School of Pharmacy and Pharmaceutical Sciences
My research focuses on praziquantel (PZQ) the only drug wildly available to treat schistosomiasis. PZQ was discovered in the early 1970’s yet its mechanism of action remains unknown. While it can greatly reduce symptoms of schistosomiasis it cannot provide a cure because it does not kill sexually immature schistosomes. To meet the WHO goal of controlling schistosomiasis by 2020, the number of PZQ tablets being administered is accelerating, increasing fears that the only therapeutic tool available may be lost to the emergence of drug resistant strains of the parasite.
My research interests are two-fold. First, to understand the mechanism of action of PZQ in order to assist the search for new compounds that might complement PZQ either through targeting independent pathways or overcoming its lack of efficacy against juveniles. This aspect of my work is performed in collaboration with Dr. Thomas Webb (SRI International) and Dr. Charles Cunningham (University of New Mexico). PZQ is administered clinically as a racemic mixture of (R)-PZQ and (S)-PZQ enantiomers with (R)-PZQ being responsible for the majority, if not all, of the drugs anthelmintic effects. Dr. Webb and his team have developed a methodology for the synthesis and purification of each enantiomer, which I use to analyze the downstream effects of (R)-PZQ and (S)-PZQ on the schistosome transcriptome and proteome to identify changes in cellular metabolism and regulation that occur on PZQ binding. In addition, Dr. Webb has synthesized a series of (R)- and (S)-PZQ analogues that covalently bind to their target that I employ to identify the PZQ binding target(s).
The second aspect of my research is to understand potential mechanisms of PZQ drug resistance. With Dr. Cunningham and Dr. Gerald Mkoji (Kenya Medical Research Institute) we have developed PZQ resistant lines of Schistosoma mansoni in the laboratory using both Kenyan field isolates and standard laboratory strains. We are using next generation sequencing to identify gene products associated with this resistance targeting expression of ATP Binding Cassette gene family members to gain insight into potential mechanisms of resistance and identify potential biological markers to monitor PZQ resistance emergence in heavily treated populations.
What is the mechanism of action of praziquantel and how might resistance strike? Future Med Chem. 2015 Apr;7(6):701-5. doi: 10.4155/fmc.15.11. No abstract available. Cupit PM, Cunningham C.
Praziquantel sensitivity of Kenyan Schistosoma mansoni isolates and the generation of a laboratory strain with reduced susceptibility to the drug. Int J Parasitol Drugs Drug Resist. 2014 Dec;4(3):296-300. doi: 10.1016/j.ijpddr.2014.09.006. Mwangi IN, Sanchez MC, Mkoji GM, Agola LE, Runo SM, Cupit PM, Cunningham C.
Design and synthesis of molecular probes for the determination of the target of the anthelmintic drug praziquantel. Bioorg Med Chem Lett. 2014 Jun 1;24(11):2469-72. doi: 10.1016/j.bmcl.2014.04.014. Epub 2014 Apr 13. Sharma LK, Cupit PM, Goronga T, Webb TR, Cunningham C.
Transcriptional analysis of Schistosoma mansoni treated with praziquantel in vitro. Mol Biochem Parasitol. 2012 Dec;186(2):87-94. doi: 10.1016/j.molbiopara.2012.09.006. Epub 2012 Sep 27. Hines-Kay J, Cupit PM, Sanchez MC, Rosenberg GH, Hanelt B, Cunningham C.
Polymorphism associated with the Schistosoma mansoni tetraspanin-2 gene. Int J Parasitol. 2011 Oct;41(12):1249-52. doi: 10.1016/j.ijpara.2011.07.007. Epub 2011 Aug 22. Cupit PM, Steinauer ML, Tonnessen BW, Eric Agola L, Kinuthia JM, Mwangi IN, Mutuku MW, Mkoji GM, Loker ES, Cunningham C.
Towards an understanding of the mechanism of action of praziquantel. Mol Biochem Parasitol. 2009 Mar;164(1):57-65. doi: 10.1016/j.molbiopara.2008.11.007. Epub 2008 Nov 28. Aragon AD, Imani RA, Blackburn VR, Cupit PM, Melman SD, Goronga T, Webb T, Loker ES, Cunningham C.