Principal Investigator (PI)
The Foundation is providing £198,940 in support.
Ramakrishna Kankanala - Milandip Karak
The in-kind contributions from GSK involves the characterization of simplified kalihinol analogues for their efficacy, safety, pharmacodynamics, and pharmacokinetics properties, initially to ensure that this series of compounds is as promising as our initial data suggest. In the medium term, further evaluations of these types will guide a medicinal chemistry effort for hit-to-lead development.
The ultimate goal of this collaborative research program is to identify antimalarial clinical candidates among analogues of the kalihinol family of isocyanoterpenes (Figure 1), an understudied class of natural products with potent activity against Plasmodium falciparum, the causative agent of the deadliest form of human malaria. Preliminary data generated in our laboratories support the premise of this research that the kalihinols could be developed as novel antimalarial agents. Our data demonstrate that (i) kalihinol natural products have potent activity against blood stages of both drug-sensitive and drug-resistant P. falciparum strains with IC50 values in the low nanomolar range; (ii) the synthetic route to these compounds has been simplified producing analogues that retain potent antimalarial activity, and there is a chemical plan in place for further synthetic simplification; (iii) the compounds have good HepG2 inhibition data and no major in silico safety alerts, and; (iv) they may exert their antimalarial activity through a novel mode of action. Building upon this body of data, we propose to delve deeply into the structure-activity relationship of these compounds, characterize their in vitro and in vivo efficacy and safety, and unravel their mode of action.