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An Amphotericin B Derivative Equally Potent to Amphotericin B and with Increased Safety.
José Marcos Falcón-González, Fabiola Eloísa Jiménez-Montejo, Ricardo Magaña, Siewert J Marrink, Rosmarbel Morales-Nava, Xavier Periole, Jorge Reyes-Esparza, Josué Rodríguez Lozada, Tania Minerva Santiago-Angelino, María Cristina Vargas González, Ignacio Regla, Mauricio Carrillo-Tripp, Mario Fernández-Zertuche, Lourdes Rodríguez-Fragoso, Iván Ortega-Blake
PLoS One 2016;11(9):e0162171. Epub 2016 Sep 28.
Instituto de Ciencias Físicas, Universidad Nacional Autónoma de México, Apartado Postal 48-3, 62251, Cuernavaca, Morelos, México.
Amphotericin B is the most potent antimycotic known to date. However due to its large collateral toxicity, its use, although long standing, had been limited. Many attempts have been made to produce derivatives with reduced collateral damage. The molecular mechanism of polyene has also been closely studied for this purpose and understanding it would contribute to the development of safe derivatives. Our study examined polyene action, including chemical synthesis, electrophysiology, pharmacology, toxicology and molecular dynamics. The results were used to support a novel Amphotericin B derivative with increased selectivity: L-histidine methyl ester of Amphotericin B. We found that this derivative has the same form of action as Amphotericin B, i.e. pore formation in the cell membrane. Its reduced dimerization in solution, when compared to Amphotericin B, is at least partially responsible for its increased selectivity. Here we also present the results of preclinical tests, which show that the derivative is just as potent as Amphotericin B and has increased safety.
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