AI Article Synopsis
- Drug resistance poses a significant challenge to malaria treatment, highlighting the need for new drug candidates, particularly those that can block transmission by targeting sexual stage parasites.
- The new compound NCATS-SM3710, a derivative of Torin 2, shows high potency and specificity against all malaria life cycle stages, including asexual parasites and late-stage gametocytes, with very low effective concentrations.
- Genetic analysis of resistant parasite lines revealed mutations in the PI4KIIIβ gene, confirming it as the target for both Torin 2 and NCATS-SM3710, thus paving the way for further development of effective multistage malaria treatments.*
Article Abstract
Drug resistance is a constant threat to malaria control efforts making it important to maintain a good pipeline of new drug candidates. Of particular need are compounds that also block transmission by targeting sexual stage parasites. Mature sexual stages are relatively resistant to all currently used antimalarials except the 8-aminoquinolines that are not commonly used due to potential side effects. Here, we synthesized a new Torin 2 derivative, NCATS-SM3710 with increased aqueous solubility and specificity for and demonstrate potent activity against all life cycle stages. NCATS-SM3710 also has low nanomolar ECs against cultured asexual parasites (0.38 ± 0.04 nM) and late stage gametocytes (5.77 ± 1 nM). Two independent NCATS-SM3710/Torin 2 resistant parasite lines produced by growth in sublethal Torin 2 concentrations both had genetic changes in PF3D7_0509800, annotated as a phosphatidylinositol 4 kinase ( PI4KIIIβ). One line had a point mutation in the putative active site (V1357G), and the other line had a duplication of a locus containing PI4KIIIβ. Both lines were also resistant to other PI4K inhibitors. In addition NCATS-SM3710 inhibited purified PI4KIIIβ with an IC of 2.0 ± 0.30 nM. Together the results demonstrate that PI4KIIIβ is the target of Torin 2 and NCATS-SM3710 and provide new options for potent multistage drug development.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551716 | PMC |
| http://dx.doi.org/10.1021/acsptsci.0c00078 | DOI Listing |
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