TY - JOUR
T1 - Localizing Antifungal Drugs to the Correct Organelle Can Markedly Enhance their Efficacy
AU - Benhamou, Raphael I.
AU - Bibi, Maayan
AU - Berman, Judith
AU - Fridman, Micha
N1 - Publisher Copyright:
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2018/5/22
Y1 - 2018/5/22
N2 - 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.
AB - 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.
KW - Candida
KW - antifungal agents
KW - azole drugs
KW - fluorogenic probes
KW - organelle-targeting drugs
UR - http://www.scopus.com/inward/record.url?scp=85046127979&partnerID=8YFLogxK
U2 - 10.1002/anie.201802509
DO - 10.1002/anie.201802509
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C2 - 29575397
AN - SCOPUS:85046127979
SN - 1433-7851
VL - 57
SP - 6230
EP - 6235
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 21
ER -