Poster Presentation Lorne Infection and Immunity 2022

The sulfonylpiperazine MMV020291 prevents red blood cell invasion through interference with actin-1/profilin dynamics in the malaria parasite Plasmodium falciparum (#127)

Madeline Dans 1 2 3 , William Nguyen 1 , Somya Mehra 2 3 , Zahra Razook 2 3 , Sujaan Das 4 , Molly Schneider 2 , Thorey Jonsdottir 2 5 , Mikha Gabriela 1 2 3 , Chris Tonkin 1 , Vanessa Mollard 5 , Geoff McFadden 5 , Danny Wilson 6 , Alyssa Barry 2 3 , Brendan Crabb AC 2 5 , Brad Sleebs 1 , Tania de Koning-Ward 3 , Paul Gilson 2 5
  1. WEHI, Parkville, VIC, Australia
  2. Burnet Institute, Melbourne, VIC, Australia
  3. Deakin University, Geelong, VIC, Australia
  4. Ludwig Maximilian University, Munich, Germany
  5. The University of Melbourne, Parkville, VIC, Australia
  6. The University of Adelaide, Adelaide, South Australia, Australia

With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. A critical process during the parasite’s asexual lifecycle is invasion of red blood cells (RBCs), a mechanism that requires many unique parasite proteins that could be exploited as druggable targets. We have recently reported the identification of a compound, MMV020291, as a specific inhibitor of RBC invasion, and successful drug resistance selection was performed. Whole genome sequencing on three MMV020291 resistant populations revealed three non-synonymous single nucleotide polymorphisms (SNPs) in two genes; two populations had SNPs in a gene encoding profilin (N154Y, K124N) and the third had a SNP present in the actin-1 gene (M356L). Using CRISPR-Cas9, we engineered these SNPs into wildtype parasites, reproducing parasite resistance to MMV020291. Monomeric actin-1 is polymerised to form filamentous strands, which are crucial for generating the force required for RBC invasion, with profilin acting to regulate this process by binding monomeric actin-1. MMV020291 appears to inhibit actin polymerisation and we are seeking to understand how the compound engages its target proteins. We have developed a series of MMV020291 analogues, achieving potency with an EC50 <100 nM, indicating the possible development for invasion blocking drugs. In addition, MMV020291 may be utilised a research tool to study the complex actin dynamics in the invading malaria parasite.