Pyridylethanol(phenylethyl)amines are non-azole, highly selective Candida albicans sterol 14α-demethylase inhibitors
2021
Authors:
Ogris, IzaZelenko, Urška
Sosič, Izidor
Gobec, Martina
Skubic, Cene
Ivanov, Marija
Soković, Marina
Kocjan, Darko
Rozman, Damjana
Golič Grdadolnik, Simona
Document Type:
Article (Published version)
,
© 2020 Elsevier Inc.
Metadata
Show full item recordAbstract:
Sterol 14α-demethylase (CYP51) is the main drug target for the treatment of fungal infections. The worldwide increase in the incidence of opportunistic fungal infections and the emerging resistance to available azole-based antifungal drugs, raise the need to develop structurally distinct and selective fungal CYP51 inhibitors. In this work we have, for the first time, investigated the binding of pyridylethanol(phenylethyl)amines to any fungal CYP51. The comparison of the binding to Candida albicans and human CYP51 studied by spectroscopic and modeling methods revealed moieties decisive for selectivity and potency and resulted in the development of highly selective derivatives with significantly increased inhibitory potency. The structure-based insight into the selectivity requirements of this new chemical class of fungal CYP51 inhibitors, their unique binding properties and the low molecular weight of lead derivatives offer novel directions for the targeted development of antifungal clinical candidates.
Keywords:
Sterol 14α-demethylase; Pyridylethanol(phenylethyl)amines; Ligand-receptor interactions; Selective Candida inhibitors; Lead designSource:
Bioorganic Chemistry, 2021, 106, 104472-Funding / projects:
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
- Slovenian Research Agency (Grant No. J1-8145, P1-0010, P1-0390, and P1-0208)
- Programme of scientific and technological cooperation between the Republic of Slovenia and the Republic of Serbia (BI-RS/14-15-015)
DOI: 10.1016/j.bioorg.2020.104472
ISSN: 0045-2068
PubMed: 33261849
WoS: 000605009300009
Scopus: 2-s2.0-85097053952
URI
https://linkinghub.elsevier.com/retrieve/pii/S0045206820317703https://radar.ibiss.bg.ac.rs/handle/123456789/4070