Pyridylethanol(phenylethyl)amines are non-azole, highly selective Candida albicans sterol 14α-demethylase inhibitors

Article abstract of DOI:10.1016/j.bioorg.2020.104472

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

Full text of DOI:10.1016/j.bioorg.2020.104472

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Pyridylethanol(phenylethyl)amines are Non-Azole, Highly Selective Candida
albicans Sterol 14α-demethylase Inhibitors
Iza Ogris, Urška Zelenko, Izidor Sosič, Martina Gobec, Cene Skubic, Marija
Ivanov, Marina Soković, Darko Kocjan, Damjana Rozman, Simona Golič
Grdadolnik
PII:
S0045-2068(20)31770-3
DOI:
https://doi.org/10.1016/j.bioorg.2020.104472
YBIOO 104472
Reference:
To appear in:
Bioorganic Chemistry
Received Date:
Accepted Date:
12 October 2020
10 November 2020
Please cite this article as: I. Ogris, U. Zelenko, I. Sosič, M. Gobec, C. Skubic, M. Ivanov, M. Soković, D. Kocjan,
D. Rozman, S. Golič Grdadolnik, Pyridylethanol(phenylethyl)amines are Non-Azole, Highly Selective Candida
albicans Sterol 14α-demethylase Inhibitors, Bioorganic Chemistry (2020), doi: https://doi.org/10.1016/j.bioorg.
2020.104472
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Pyridylethanol(phenylethyl)amines are Non-Azole, Highly Selective
Candida albicans Sterol 14α-demethylase Inhibitors
Iza Ogris a#, Urška Zelenkoa#‡, Izidor Sosič b#, Martina Gobecb, Cene Skubicc, Marija Ivanovd,
Marina Sokovićd, Darko Kocjana, Damjana Rozmanc, and Simona Golič Grdadolnika*
aLaboratory for Molecular Structural Dynamics, Theory department, National Institute of
Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia
bFaculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
cCenter for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of
Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
dInstitute for Biological Research "Siniša Stanković"- National Institute of Republic of Serbia,
University of Belgrade, Bulevar Despota Stefana 142, 11000 Belgrade, Serbia
‡ Present address: Pavčkova ulica 3, 8000 Novo mesto, Slovenia
# These authors contributed equally to this work.
*Corresponding Author: Phone: +386 1 4760 409. Fax: +386 1 4760 300.
Email: simona.grdadolnik@ki.si
1

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ABSTRACT
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 design
2

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1. INTRODUCTION
Sterol 14α-demethylase (CYP51) belongs to the cytochrome P450 superfamily. It is a
crucial enzyme in the sterol biosynthetic pathway, where it catalyzes the oxidative removal of
the 14α-methyl group from sterol precursors. CYP51 has a high substrate specificity with only
five naturally occurring, structurally similar 14α-methylsterols as substrates [1]. While
prokaryotic CYP51s are soluble proteins, eukaryotic ones are membrane-bound. The final
products of sterol biosynthesis are essential structural components of eukaryotic membranes:
cholesterol in animals, ergosterol in fungi, and phytosterols in plants. The essential nature of
sterol biosynthesis makes CYP51 an important target for drugs to treat infections in humans,
animals and plants [2, 3]. For the treatment of human infections, selectivity towards microbial
or fungal CYP51 is of crucial importance, since co-inhibition of human CYP51 (hCYP51)
would result in the inhibition of cholesterol synthesis and an uncontrolled accumulation of
toxic sterols. In the mouse, inactivation of the liver CYP51 enzyme leads to an accumulation
of lanosterol and 24,25-dehydrolanosterol and to progressive liver pathology [4, 5]. Due to the
potentially toxic effect of sterols and their ability to activate nuclear receptors [6], several
drugs targeting this biosynthetic pathway in humans have been discontinued [7] and more
attention has been paid to the use of such drug candidates in microbial systems.
Azoles are the most broadly known CYP51 inhibitors and the most widely used antifungals
in clinical medicine and agriculture. The supposed basis for the efficacy and safety of azoles
is their selective inhibition of fungal CYP51 over the human ortholog. However,
measurements of enzyme inhibition on the purified hCYP51 and Candida albicans CYP51
(CaCYP51) showed that the selectivity of clinical imidazole ketoconazole and triazole
itraconazole is an order of magnitude lower than expected based on previous measurements
on microsomal preparations, the difference of the binding affinity is actually less than 10-fold
[8]. In general, the triazoles have an improved affinity for fungal over mammalian P450
enzymes compared to the imidazoles. Therefore, clinical triazoles (itraconazole, fluconazole,
voriconazole, posaconazole and isavuconazole) have broad application in antifungal therapy
whereas for Ketoconazole treatment of systemic human infections is limited [9, 10].
The three-dimensional structures of the CYP51 proteins across biological kingdoms are
highly similar despite the low primary sequence identities that can be as low as 22-30 %. The
most characteristic feature of the CYP51 structure is the rigidity of the substrate binding
cavity, which together with highly similar general fold probably helps to maintain their
strictly specific three-step catalytic reaction [2]. First crystal structures of eukaryotic CYP51
3