Hameed P Shahul, Solapure Suresh, Patil Vikas, Henrich Philipp P, Magistrado Pamela A, Bharath Sowmya, Murugan Kannan, Viswanath Pavithra, Puttur Jayashree, Srivastava Abhishek, Bellale Eknath, Panduga Vijender, Shanbag Gajanan, Awasthy Disha, Landge Sudhir, Morayya Sapna, Koushik Krishna, Saralaya Ramanatha, Raichurkar Anandkumar, Rautela Nikhil, Roy Choudhury Nilanjana, Ambady Anisha, Nandishaiah Radha, Reddy Jitendar, Prabhakar K R, Menasinakai Sreenivasaiah, Rudrapatna Suresh, Chatterji Monalisa, Jiménez-Díaz María Belén, Martínez María Santos, Sanz Laura María, Coburn-Flynn Olivia, Fidock David A, Lukens Amanda K, Wirth Dyann F, Bandodkar Balachandra, Mukherjee Kakoli, McLaughlin Robert E, Waterson David, Rosenbrier-Ribeiro Lyn, Hickling Kevin, Balasubramanian V, Warner Peter, Hosagrahara Vinayak, Dudley Adam, Iyer Pravin S, Narayanan Shridhar, Kavanagh Stefan, Sambandamurthy Vasan K
Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India.
Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA.
Nat Commun. 2015 Mar 31;6:6715. doi: 10.1038/ncomms7715.
The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg(-1) and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.
对一线药物耐药的恶性疟原虫（Pf）菌株广泛出现，促使人们寻找具有新作用机制的速效药物。在此，我们报告新型抗疟化合物三氨基嘧啶（TAPs）的发现与优化，这些化合物是通过针对Pf血液阶段的表型筛选获得的。临床候选药物（化合物12）在Pf疟疾小鼠模型中有效，ED99<30mg kg⁻¹，在豚鼠和大鼠中显示出良好的体内安全范围。预计在人体中的半衰期为36小时，单剂量260mg可能足以维持治疗性血药浓度4 - 5天。耐药突变体的全基因组测序表明液泡ATP合酶是对TAPs耐药的遗传决定因素。我们的研究突出了TAPs与其他处于临床开发阶段的药物联合用于单剂量治疗Pf疟疾的潜力。
