UCT943 / University of Cape Town, Medicines for Malaria Venture - LARVOL DELTA

Susceptibility of Plasmodium falciparum isolates from eastern Uganda to ganaplacide and phosphatidylinositol 4-kinase inhibitors (ASTMH 2023) - "Median IC 50 s for two lead Pf PI4K inhibitors, MMV048 and UCT943, were 65 and 11 n M, respectively. No mutations were observed in Pf ACT or Pf UGT. Overall, Ugandan P. falciparum isolates were highly susceptible to these compounds under development as next-generation antimalarials, consistent with a lack of pre-existing or novel resistance-conferring mutations in circulating Ugandan parasites."

Infectious Disease

Susceptibility of Plasmodium falciparum isolates from eastern Uganda to antimalarial compounds under development (ASTMH 2022) - "In general, field isolates were highly susceptible, with median IC50s in the low nM range for compounds targeting PfCYTb (ELQ300, 13 nM); PfDHODH (DSM265, 3.6 nM; DSM421, 20 nM; DSM632, 9.8 nM; DSM705, 11 nM; DSM1049, 22 nM; BRD1331 13 nM), PfEF2 (DDD498, 0.6 nM); PfPheRS (BRD5018, 1.6 nM); and PfPI4K (MMV048, 60 nM; UCT943, 11 nM). Three mutations (N957H, I876V and Y883H) in PfPI4K were associated with slightly decreased susceptibility to MMV048 (median IC50 WT vs mutant: 55 nM vs 74 nM for N957H, 61 nM vs 75 nM for I876V, and 60 nM vs 77 nM for Y883H). Overall, Ugandan P. falciparum isolates were highly susceptible to 11 compounds under development as next-generation antimalarials, consistent with a lack of pre-existing or novel resistance-conferring mutations in circulating Ugandan parasites."

Infectious Disease • Malaria

Automatic reconstruction of metabolic pathways from identified biosynthetic gene clusters. (PubMed, BMC Bioinformatics) - "With this pipeline we pave the way for an extended use of genome-scale metabolic models in strain design of heterologous expression hosts. In this context, we identified generic knockout targets for the increased production of heterologous compounds. However, as the predicted increase is minor for any of the single-reaction knockout targets, these results indicate that more sophisticated strain-engineering strategies are necessary for the development of efficient BGC expression hosts."

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