Lanosterol 14α-demethylase (CYP51)/histone deacetylase (HDAC) dual inhibitors for treatment of Candida tropicalis and Cryptococcus neoformans infections

  • Eur J Med Chem. 2021 Oct 5;221:113524. doi: 10.1016/j.ejmech.2021.113524.
Tianbao Zhu  1 ,  Xi Chen  2 ,  Chenglan Li  3 ,  Jie Tu  3 ,  Na Liu  4 ,  Defeng Xu  5 ,  Chunquan Sheng  6
Affiliations
  • 1. National & Local Joint Engineering Research Center for High-efficiency Refining and High-quality Utilization of Biomass, School of Pharmacy, 1 Gehu Road, Changzhou University, Changzhou, 213164, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
  • 2. Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, 1 Xuefu Avenue, Xi'an, 710127, China.
  • 3. School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
  • 4. School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: [email protected].
  • 5. National & Local Joint Engineering Research Center for High-efficiency Refining and High-quality Utilization of Biomass, School of Pharmacy, 1 Gehu Road, Changzhou University, Changzhou, 213164, China. Electronic address: [email protected].
  • 6. School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: [email protected].
PMID: 33992927 DOI: 10.1016/j.ejmech.2021.113524
Abstract

Invasive Fungal infections remain a challenge due to lack of effective Antifungal agents and serious drug resistance. Discovery of Antifungal agents with novel Antifungal mechanism is important and urgent. Previously, we designed the first CYP51/HDAC dual inhibitors with potent activity against resistant Candida albicans infections. To better understand the Antifungal spectrum and synergistic mechanism, herein new CYP51/HDAC dual inhibitors were designed which showed potent in vitro and in vivo Antifungal activity against C. neoformans and C. tropicalis infections. Antifungal mechanism studies revealed that the CYP51/HDAC dual inhibitors acted by inhibiting various virulence factors of C. tropicalis and C. neoformans and down-regulating resistance-associated genes. This study highlights the potential of CYP51/HDAC dual inhibitors as a promising strategy for the discovery of novel broad-spectrum Antifungal agents.

Keywords
Antifungal; CYP51/HDAC dual Inhibitors; Candida tropicalis; Cryptococcus neoformans; Virulence factors.
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