2. Academic Validation
  3. Redesigning of the cap conformation and symmetry of the diphenylethyne core to yield highly potent pan-genotypic NS5A inhibitors with high potency and high resistance barrier

Redesigning of the cap conformation and symmetry of the diphenylethyne core to yield highly potent pan-genotypic NS5A inhibitors with high potency and high resistance barrier

  • Eur J Med Chem. 2022 Feb 5;229:114034. doi: 10.1016/j.ejmech.2021.114034.
Mennatallah Abdallah 1,  Mostafa M Hamed 2,  Efseveia Frakolaki 3,  Sotirios Katsamakas 4,  Niki Vassilaki 3,  Ralf Bartenschlager 5,  Grigoris Zoidis 6,  Anna K H Hirsch 7,  Mohammad Abdel-Halim 8,  Ashraf H Abadi 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt.
  • 2 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University Campus E8.1, 66123, Saarbrücken, Germany.
  • 3 Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, 11521, Athens, Greece.
  • 4 School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771, Athens, Greece.
  • 5 Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany; German Center for Infection Research, Heidelberg Partner Site, Germany.
  • 6 School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771, Athens, Greece. Electronic address: zoidis@pharm.uoa.gr.
  • 7 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University Campus E8.1, 66123, Saarbrücken, Germany; Department of Pharmacy, Saarland University, Campus E8.1, Saarbrücken, 66123, Germany.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt. Electronic address: mohammad.abdel-halim@guc.edu.eg.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt. Electronic address: ashraf.abadi@guc.edu.eg.
PMID: 34959173 DOI: 10.1016/j.ejmech.2021.114034
Abstract

Herein, we report the discovery of several NS5A inhibitors with potency against HCV genotype 1b in the picomolar range. Compounds (15, 33) were of extremely high potency against HCV genotype 1b (EC50 ≈ 1 pM), improved activity against genotype 3a (GT 3a) and good metabolic stability. We studied the impact of changing the cap conformation relative to the diphenylethyne core and/or compound symmetry on both potency and metabolic stability. The analogs obtained exhibited improved potency against HCV genotypes 1a, 1b, 3a and 4a compared to the clinically approved candidate daclatasvir with EC50 values in the low picomolar range and SI50s > 7 orders of magnitude. Compound 15, a symmetrically m-, m'-substituted diphenyl ethyne analog, was 150-fold more potent than daclatasvir against GT 3a, while compound 33, an asymmetrically m-, p-substituted diphenyl ethyne analog, was 35-fold more potent than daclatasvir against GT 3a. In addition, compound 15 exhibited a higher resistance barrier than daclatasvir against genotype 1b.

Keywords

Cap conformation; Diphenylethyne Core; Hepatitis C virus; NS5A inhibitors; Pan-genotypic activity; Resistance mutations; Spatial orientation.

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