Localizing Antifungal Drugs to the Correct Organelle Can Markedly Enhance their Efficacy.
Angew Chem Int Ed Engl
; 57(21): 6230-6235, 2018 05 22.
Article
em En
| MEDLINE
| ID: mdl-29575397
ABSTRACT
A critical aspect of drug design is optimal target inhibition by specifically delivering the drug molecule not only to the target tissue or cell but also to its therapeutically active site within the cell. This study demonstrates, as a proof of principle, that drug efficacy can be increased considerably by a structural modification that targets it to the relevant organelle. Specifically, by varying the fluorescent dye segment an antifungal azole was directed from the fungal cell mitochondria to the endoplasmic reticulum (ER), the organelle that harbors the drug target. The ER-localized azole displayed up to two orders of magnitude improved antifungal activity and also dramatically reduced the growth of drug-tolerant fungal subpopulations in a panel of Candida species, which are the most prevalent causes of serious human fungal infections. The principle underlying the "target organelle localization" approach provides a new paradigm to improve drug potency and replenish the limited pipeline of antifungal drugs.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Azóis
/
Candida
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Desenho de Fármacos
/
Organelas
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Antifúngicos
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Israel