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. 2023 Nov 22;11(12):2837.
doi: 10.3390/microorganisms11122837.

Is the C-Terminal Domain an Effective and Selective Target for the Design of Hsp90 Inhibitors against Candida Yeast?

Célia Rouges  1 , Mohammad Asad  2 , Adèle D Laurent  2 , Pascal Marchand  1 , Patrice Le Pape  1
Affiliations

Is the C-Terminal Domain an Effective and Selective Target for the Design of Hsp90 Inhibitors against Candida Yeast?

Célia Rouges et al. Microorganisms. .

Abstract

Improving the armamentarium to treat invasive candidiasis has become necessary to overcome drug resistance and the lack of alternative therapy. In the pathogenic fungus Candida albicans, the 90-kDa Heat-Shock Protein (Hsp90) has been described as a major regulator of virulence and resistance, offering a promising target. Some human Hsp90 inhibitors have shown activity against Candida spp. in vitro, but host toxicity has limited their use as antifungal drugs. The conservation of Hsp90 across all species leads to selectivity issues. To assess the potential of Hsp90 as a druggable antifungal target, the activity of nine structurally unrelated Hsp90 inhibitors with different binding domains was evaluated against a panel of Candida clinical isolates. The Hsp90 sequences from human and yeast species were aligned. Despite the degree of similarity between human and yeast N-terminal domain residues, the in vitro activities measured for the inhibitors interacting with this domain were not reproducible against all Candida species. Moreover, the inhibitors binding to the C-terminal domain (CTD) did not show any antifungal activity, with the exception of one of them. Given the greater sequence divergence in this domain, the identification of selective CTD inhibitors of fungal Hsp90 could be a promising strategy for the development of innovative antifungal drugs.

Keywords: Candida sp.; Hsp90; antifungal targets.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of the Hsp90 inhibitors.
Figure 2
Figure 2
Multiple sequences alignment of human Hsp90 alpha, Trypanosoma brucei Hsp83, Saccharomyces cerevisiae. Boxes represent residues or sequences of residues susceptible to interaction with Hsp90 inhibitors and different between humans and Candida sp. (black), different between the four Candida species (green), or different only for one Candida species (red). The black dots represent residues or sequences of residues susceptible to interaction with ATP and/or Hsp90 inhibitors and are identical between humans and yeast. NTD, N-Terminal Domain; MD, Median Domain; CTD, C-Terminal Domain.
Figure 3
Figure 3
Structure superposition of HSP90 Homo sapiens (pdb id: 7L7I) with Candida albicans HSP90 model obtained from AlphaFold prediction. (a) Three domains, the N-terminal domain (NTD), Median domain (MD), and C-terminal domain (CTD), are represented. (b) Superimposed structure of C-terminal domain of HSP90 of Homo sapiens (Red) and Candida albicans (Green). The RMSD value between both structures is ~1.0 Å. (c) Homo sapiens and C. albicans residues susceptible to interact with HSP90 inhibitors.
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