A New Set of Chemical Starting Points with Plasmodium falciparum Transmission-Blocking Potential for Antimalarial Drug Discovery

Abstract

The discovery of new antimalarials with transmission blocking activity remains a key issue in efforts to control malaria and eventually eradicate the disease. Recently, high-throughput screening (HTS) assays have been successfully applied to Plasmodium falciparum asexual stages to screen millions of compounds, with the identification of thousands of new active molecules, some of which are already in clinical phases. The same approach has now been applied to identify compounds that are active against P. falciparum gametocytes, the parasite stage responsible for transmission. This study reports screening results for the Tres Cantos Antimalarial Set (TCAMS), of approximately 13,533 molecules, against P. falciparum stage V gametocytes. Secondary confirmation and cytotoxicity assays led to the identification of 98 selective molecules with dual activity against gametocytes and asexual stages. Hit compounds were chemically clustered and analyzed for appropriate physicochemical properties. The TCAMS chemical space around the prioritized hits was also studied. A selection of hit compounds was assessed ex vivo in the standard membrane feeding assay and demonstrated complete block in transmission. As a result of this effort, new chemical structures not connected to previously described antimalarials have been identified. This new set of compounds may serve as starting points for future drug discovery programs as well as tool compounds for identifying new modes of action involved in malaria transmission.

New developments in anti-malarial target candidate and product profiles

“…Confirmation of the effect on transmission reduction is measured with the standard membrane feeding assay (SMFA) that measures both the number of oocysts per midgut (intensity of infection) and the number of mosquitoes infected (prevalence of infection). Considerable improvements in this assay have been made in the last 4 years [149, 150], and its outcome is now part of the standard decision-making process. Accurate efficacy prediction of the SMFA results from the gametocyte counts is currently not possible, so the recommended strategy is to use the gametocyte data as a filter to select compounds that impact transmission, but to make decisions based on SMFA data at the lead-to-candidate stage.…”

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Emergence of resistance to first‐line treatments, including artemisinin combination therapies, continues to undermine the considerable progress made in eradicating infection, and puts into sharp focus the critical need to drug new targets with novel scaffolds . The Pathogen Box contains 125 compounds which possess antiplasmodial activity, many of which were identified from phenotypic screening of the GSK Tres Cantos Anti‐Malarial Set (TCAMS) …”

Discovering New Transmission-Blocking Antimalarial Compounds: Challenges and Opportunities

“…Additionally, certain chemical classes (e.g. anti-malarial activity [20,29,32,33], supporting the notion that such strategies could yield transmission-blocking compounds. Certain scaffolds (e.g.…”

“…Similar to the Malaria Box results [23], the majority (>80-90%) of compounds targeting the asexual parasite are ineffective against stage IV/V gametocytes [32] with little correlation between the anti-asexual and gametocytocidal activity [23,33,34].…”