{"doi":"10.14293/cgmp.24000045.v1","title":"PfPKG inhibitors for malaria chemoprevention","abstract":"

Malaria, caused by protozoan parasites of the Plasmodium genus, killed over 600,000 people and infected another 250 million in 2023. The toll from malaria is likely to increase due to the spread of drugresistancein the parasite population and insecticide-resistance in the mosquito vectors. Progress towards controlling malaria requires new drugs will novel mechanisms of action. One promising drug target is the P. falciparum cGMP-dependent protein kinase (PfPKG), the major effector of cGMP signaling in the parasite. It is essential for viability at several steps of the parasite’s complex life cycle. Its genetic or pharmacological inhibition blocks invasion and exit of parasites from host hepatocytes and erythrocytes, making it an attractive target for achieving pre-exposure prophylaxis against malaria. Towards this end, we defined the structure-activity relationship of a pyrrole series for PfPKG inhibition. Key pharmacophores were modified to enable full exploration of chemical diversity and to gain knowledge about an ideal core scaffold. In vitro potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the parasite enzyme. Cellular acitivity of compounds was determined against two parasite stages. Their specificity was evaluated using transgenic parasites expressing PfPKG carrying a substituted \"gatekeeper\" residue that occludes the compound binding site. The structure of PfPKG bound to an inhibitor was solved, and modeling using this structure together with computational tools was utilized to understand SAR and establish a rational strategy for subsequent lead optimization.","journal":null,"year":2024,"id":498254,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":389130,"name":"Purnima Bhanot","orcid":"0000-0001-5116-6973","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:09:38.543544Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}