Inhibitors of ApiAP2 protein DNA binding exhibit multistage activity against Plasmodium parasites

• DOI: 10.1371/journal.ppat.1010887
• Publication Date: 2022-10-12T17:40:56Z
• Authors: Timothy James Rus...; Erandi K. De Silva; Valerie M. Crowley; Kathryn Shaw-Saliba; Namita Dube; Gabrielle Josling; Charisse Flerida ...; Irene Kouskoumvekaki; Gianni Panagiotou; Jacquin C. Niles; Marcelo Jacobs-Lo...; C. Denise Okafor; Francisco-Javier ...; Manuel Llinás
• Keywords: Plasmodium (life cycle); DNA binding site

Plasmodium parasites are reliant on the Apicomplexan AP2 (ApiAP2) transcription factor family to regulate gene expression programs. DNA binding domains have no homologs in human or mosquito host genomes, making them potential antimalarial drug targets. Using an in-silico screen dock thousands of small molecules into crystal structure AP2-EXP (Pf3D7_1466400) domain (PDB:3IGM), we identified putative interacting compounds. Four compounds were found block by and at least one additional ApiAP2 protein. Our top competitor compound perturbs transcriptome P . falciparum trophozoites results a decrease abundance log 2 fold change > for 50% (46/93) target genes. Additionally, two multi-stage anti- activity against blood stage parasites. In summary, describe novel set that interact with domains. These may be used future chemical genetic interrogation proteins serve as starting points new class therapeutics.