Calcineurin Inhibitor CN585 Exhibits Off-Target Effects in the Human Fungal Pathogen Aspergillus fumigatus.
Calcineurin Inhibitor CN585 Exhibits Off-Target Effects in the Human Fungal Pathogen Aspergillus fumigatus.
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钙调蛋白抑制剂CN585在人类真菌病原体烟草中表现出脱靶作用。
DOI：
10.3390/jof8121281
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发表时间：
2022-12-07
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影响因子：
--
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中科院分区：
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钙调磷酸酶（CN）是一种有吸引力的抗真菌靶点，因为它对真菌病原体的生长、应激反应、耐药性和毒力至关重要。免疫抑制药物他克莫司（FK506）和环孢素A （CsA）具有抑菌作用，通过与各自的亲免疫蛋白、FK506结合蛋白（FKBP12）和亲环蛋白（CypA）结合特异性抑制CN。我们专注于基于CN结构的方法，用于开发非免疫抑制FK506类似物作为抗真菌治疗药物。在这里，我们研究了新型CN抑制剂CN585对人类病原体烟曲霉生长的影响，烟曲霉是侵袭性曲霉病的最常见原因。出乎意料的是，与FK506相比，CN585对烟曲霉野生型和耐唑、耐棘白菌素菌株表现出脱靶效应。与FK506和CsA不同，烟曲霉CN、FKBP12、CypA突变体（ΔcnaA、Δfkbp12、ΔcypA）和各种FK506抗性突变体均对CN585敏感。此外，与FK506相反，CN585不抑制cn依赖性转录因子（CrzA-GFP）的胞质向核易位。CN585与人类和烟曲霉CN复合物的分子对接揭示了人类CN与烟曲霉CN潜在结合位点的差异。我们的研究结果表明，CN585可能是CN的非特异性抑制剂，其抗真菌活性机制尚未明确。
Calcineurin (CN) is an attractive antifungal target as it is critical for growth, stress response, drug resistance, and virulence in fungal pathogens. The immunosuppressive drugs, tacrolimus (FK506) and cyclosporin A (CsA), are fungistatic and specifically inhibit CN through binding to their respective immunophilins, FK506-binding protein (FKBP12), and cyclophilin (CypA). We are focused on CN structure-based approaches for the development of non-immunosuppressive FK506 analogs as antifungal therapeutics. Here, we examined the effect of the novel CN inhibitor, CN585, on the growth of the human pathogen Aspergillus fumigatus, the most common cause of invasive aspergillosis. Unexpectedly, in contrast to FK506, CN585 exhibited off-target effect on A. fumigatus wild-type and the azole- and echinocandin-resistant strains. Unlike with FK506 and CsA, the A. fumigatus CN, FKBP12, CypA mutants (ΔcnaA, Δfkbp12, ΔcypA) and various FK506-resistant mutants were all sensitive to CN585. Furthermore, in contrast to FK506 the cytosolic to nuclear translocation of the CN-dependent transcription factor (CrzA-GFP) was not inhibited by CN585. Molecular docking of CN585 onto human and A. fumigatus CN complexes revealed differential potential binding sites between human CN versus A. fumigatus CN. Our results indicate CN585 may be a non-specific inhibitor of CN with a yet undefined antifungal mechanism of activity.
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影响因子：
64.5
作者：
LIU, J;FARMER, JD;SCHREIBER, SL
通讯作者：
SCHREIBER, SL
影响因子：
56.9
作者：
ALBERG, DG;SCHREIBER, SL
通讯作者：
SCHREIBER, SL
影响因子：
5.3
作者：
Caselli, Emilia;Fini, Francesco;Prati, Fabio
通讯作者：
Prati, Fabio
影响因子：
3.5
作者：
Juvvadi, Praveen R.;Pemble, Charles W.;Steinbach, William J.
通讯作者：
Steinbach, William J.
DOI：
10.1073/pnas.192206699
发表时间：
2002-09-17
影响因子：
11.1
作者：
Huai, Q;Kim, HY;Ke, HM
通讯作者：
Ke, HM