Optimization of antimalarials targeting multiple life stages of the parasite

PROJECT SUMMARY/ABSTRACT
The malaria parasite is one of the most deadly eukaryotic pathogens and more than 40% of the world's population
is at risk of contracting malaria. Due to growing resistance to currently available medications, there is a pressing
medical need for new drugs to prevent and treat malaria infection. This grant application focuses on the
optimization of two novel antimalarials (2a and (R)-3a) to target multiple life stages of the parasite that emerged
from our previous work on the Malaria Box compound MMV008138 that targets the apicoplast. These
compounds were identified using a combination of atomic property field-based virtual ligand screening (VLS) of
a library of 5 million publicly available compounds and synthetic chemistry campaigns. Although 2a and (R)-3a
bear a structural resemblance to MMV008138 and kill asexual blood-stages, their mechanism of action is
independent of the apicoplast. In addition, whereas MMV008138 only affects asexual blood-stages, 2a also kills
Stage V gametocytes, and (R)-3a weakly kills Plasmodium berghei liver-stages. For each of the two novel
compound series, we will explore: i) structure activity relationships that control potency, cellular selectivity, and
efficacy; ii) structure property relationships that govern adsorption, distribution, metabolism, and excretion; and
iii) their potential mechanisms of action and resistance. The overarching goal of this project is to prioritize
preclinical leads having novel mechanism of action, high selectivity for Plasmodium versus the human host, and
physiochemical properties that are compatible with development of an orally available drug candidate. The two
principal goals of this R01 proposal are to: 1) structurally modify 2a (lead) and (R)-3a (hit) to optimize in vitro
asexual blood-stage potencies in addition to gametocicydal and/or liver stage activities, drug-like properties, and
pharmacokinetics, achieving in vivo P. berghei-infected mice efficacy with a single oral dose ED90 ≤ 10 mg/kg
for the 2a analogs (late lead) and an ED90 ≤ 40 mg/kg/day with 1-3 oral doses for the (R)-3a series (early lead),
and 2) identify the antimalarial mechanisms of action and resistance of 2a and (R)-3a (or their more potent
analogs) by chemoproteomic and resistance-selection approaches, respectively. The ancillary goal of this
proposal is to develop structure-activity relationships (SAR) for the P. falciparum gametocytocidal potency and
P. berghei liver-stage potency of these two series, and to determine consensus pharmacophores for multi-stage
activities (asexual blood-stage potencies plus gametocytocidal and/or liver-stage potencies). Efficacious
compounds identified in this way will thus be well-positioned for further preclinical development.

Grant Number: 5R01AI157445-06
NIH Institute/Center: NIH
Principal Investigator: Paul Carlier