Michael Zhuo Wang
Department of Pharmaceutical Chemistry
University of Kansas
Expression and Function of CYP5122A1, an Essential Leishmanial Sterol Biosynthesis Enzyme (2016-2017)
Leishmaniasis is a serious human disease caused by protozoan trypanosomatid parasites belonging to the genus Leishmania. The disease threatens about 350 million people in 88 countries. About two million new cases of leishmaniasis occur every year. Current antileishmanial drugs have significant liabilities, including teratogenicity, increasing failure rates and high costs. As such, a safe, effective and orally active antileishmanial drug is a major unmet medical need. CYP5122A1 is a novel cytochrome P450 (CYP) enzyme that is essential for the survival of L. donovani, the causative agent for visceral leishmaniasis, the most dangerous and fatal form of the disease.
Previous results suggest that the enzyme plays an essential (but as yet unknown) role in ergosterol biosynthesis in the parasite. We hypothesize CYP5122A1 plays a key role in the leishmanial sterol biosynthesis by catalyzing the lanosterol 14α-demethylation and CYP5122A1 inhibitors represent a novel chemotherapeutic approach against leishmaniasis. To test this hypothesis, two specific aims will be carried out in this proposed pilot project: first, to express and purify leishmanial CYP5122A1 and CYP51 in Escherichia coli; second, to evaluate the functional role of CYP5122A1 in lanosterol metabolism.
If successfully completed, the proposed experiments will improve our understanding of the essential role of CYP5122A1 in maintaining the leishmanial sterol homeostasis and establish resources necessary to screen chemical libraries for specific and potent inhibitors of CYP5122A1. The to-be-acquired knowledge and resources will provide a foundation to pursue the long-term objective of our research program to develop CYP5122A1 inhibitors as a novel chemotherapeutic approach against leishmaniasis.