PT  - JOURNAL ARTICLE
AU  - Jolyn E. Gisselberg
AU  - Zachary Herrera
AU  - Lindsey Orchard
AU  - Manuel Llinás
AU  - Ellen Yeh
TI  - A specific non-bisphosphonate inhibitor of the bifunctional farnesyl/geranylgeranyl diphosphate synthase in malaria parasites
AID  - 10.1101/134338
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 134338
4099  - http://biorxiv.org/content/early/2017/07/21/134338.short
4100  - http://biorxiv.org/content/early/2017/07/21/134338.full
AB  - Isoprenoid biosynthesis is essential for Plasmodium falciparum (malaria) parasites and contains multiple validated antimalarial drug targets, including a bifunctional farnesyl and geranylgeranyl diphosphate synthase (FPPS/GGPPS). We identified MMV019313 as an inhibitor of PfFPPS/GGPPS. Though PfFPPS/GGPPS is also inhibited by a class of bisphosphonate drugs, MMV019313 has significant advantages for antimalarial drug development. MMV019313 has superior physicochemical properties compared to charged bisphosphonates that have poor bioavailability and strong bone affinity. We also show that it is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition of PfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes-of-inhibition against PfFPPS/GGPPS. Altogether MMV019313 is the first specific, non-bisphosphonate inhibitor of PfFPPS/GGPPS. Our findings uncover a new small molecule binding site in this important antimalarial drug target and provide a promising starting point for development of Plasmodium-specific FPPS/GGPPS inhibitors.