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Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate
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 fro...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Nature Pub. Group
2015
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389225/ https://www.ncbi.nlm.nih.gov/pubmed/25823686 http://dx.doi.org/10.1038/ncomms7715 |
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| author | 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. |
| author_facet | 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. |
| author_sort | Hameed P., Shahul |
| collection | PubMed |
| description | 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 ED(99) <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. |
| format | Online Article Text |
| id | pubmed-4389225 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2015 |
| publisher | Nature Pub. Group |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-43892252015-04-17 Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate 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. Nat Commun Article 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 ED(99) <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. Nature Pub. Group 2015-03-31 /pmc/articles/PMC4389225/ /pubmed/25823686 http://dx.doi.org/10.1038/ncomms7715 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| spellingShingle | Article 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. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate |
| title | Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate |
| title_full | Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate |
| title_fullStr | Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate |
| title_full_unstemmed | Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate |
| title_short | Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate |
| title_sort | triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389225/ https://www.ncbi.nlm.nih.gov/pubmed/25823686 http://dx.doi.org/10.1038/ncomms7715 |
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