Dataset Information

UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria.

ABSTRACT: The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2R? null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.

SUBMITTER: Brunschwig C

PROVIDER: S-EPMC6125526 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria.

Brunschwig Christel C Lawrence Nina N Taylor Dale D Abay Efrem E Njoroge Mathew M Basarab Gregory S GS Le Manach Claire C Paquet Tanya T Cabrera Diego Gonzàlez DG Nchinda Aloysius T AT de Kock Carmen C Wiesner Lubbe L Denti Paolo P Waterson David D Blasco Benjamin B Leroy Didier D Witty Michael J MJ Donini Cristina C Duffy James J Wittlin Sergio S White Karen L KL Charman Susan A SA Jiménez-Díaz Maria Belén MB Angulo-Barturen Iñigo I Herreros Esperanza E Gamo Francisco Javier FJ Rochford Rosemary R Mancama Dalu D Coetzer Theresa L TL van der Watt Mariëtte E ME Reader Janette J Birkholtz Lyn-Marie LM Marsh Kennan C KC Solapure Suresh M SM Burke John E JE Burke John E JE McPhail Jacob A JA Vanaerschot Manu M Fidock David A DA Fish Paul V PV Siegl Peter P Smith Dennis A DA Wirjanata Grennady G Wirjanata Grennady G Noviyanti Rintis R Price Ric N RN Marfurt Jutta J Silue Kigbafori D KD Street Leslie J LJ Chibale Kelly K

Antimicrobial agents and chemotherapy 20180827 9

The 2-aminopyridine MMV048 was the first drug candidate inhibiting <i>Plasmodium</i> phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver ...[more]

PMID: 29941635

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Project description:Well-defined molecular resistance markers are available for a range of antimalarial drugs, and molecular surveillance is increasingly important for monitoring antimalarial drug resistance. Different genotyping platforms are available, but these have not been compared in detail. We compared Targeted Amplicon Deep sequencing (TADs) using Ion Torrent PGM with Illumina MiSeq for the typing of antimalarial drug resistance genes. We developed and validated protocols to type the molecular resistance markers pfcrt, pfdhfr, pfdhps, pfmdr1, pfkelch, and pfcytochrome b, in Plasmodium falciparum for the Ion Torrent PGM and Illumina MiSeq sequencing platforms. With P. falciparum 3D7 and K1 as reference strains, whole blood samples (N = 20) and blood spots from Rapid Diagnostic Test (RDT) samples (N = 5) from patients with uncomplicated falciparum malaria from Ubon Ratchathani were assessed on both platforms and compared for coverage (average reads per amplicon), sequencing accuracy, variant accuracy, false positive rate, false negative rate, and alternative allele detection, with conventional Sanger sequencing as the reference method for SNP calling. Both whole blood and RDT samples could be successfully sequenced using the Ion Torrent PGM and Illumina MiSeq platforms. Coverage of reads per amplicon was higher with Illumina MiSeq (28,886 reads) than with Ion Torrent PGM (1754 reads). In laboratory generated artificial mixed infections, the two platforms could detect the minor allele down to 1% density at 500X coverage. SNPs calls from both platforms were in complete agreement with conventional Sanger sequencing. The methods can be multiplexed with up to 96 samples per run, which reduces cost by 86% compared to conventional Sanger sequencing. Both platforms, using the developed TAD protocols, provide an accurate method for molecular surveillance of drug resistance markers in P. falciparum, but Illumina MiSeq provides higher coverage than Ion Torrent PGM.

Dataset Information

UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria.

Publications

UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria.

Similar Datasets

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