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Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

Xiong Xie1,2, Qiaoshuai Lan3, Jinyi Zhao2,4

  • 1Drug Discovery and Design Center, State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Signal Transduction and Targeted Therapy
|March 5, 2024
PubMed

Insights

Two novel compounds, 14a and 14b, effectively inhibit host proteases Cathepsin L and calpain-1, demonstrating broad-spectrum antiviral activity against SARS-CoV-2 variants and HCoV-OC43, with promising anti-inflammatory effects.

Area of Science:

  • Virology
  • Drug Discovery
  • Immunology

Background:

  • Emerging coronaviruses pose a global health threat, necessitating novel therapeutic strategies beyond existing vaccines and antivirals.
  • Host-targeting antivirals offer a promising approach to combat viral resistance and future outbreaks.
  • Cathepsin L (CTSL) and calpain-1 (CAPN1) are critical host proteases involved in coronavirus entry and immune responses.

Purpose of the Study:

  • To identify and characterize novel dual inhibitors targeting CTSL and CAPN1 for broad-spectrum coronavirus treatment.
  • To evaluate the in vitro and in vivo antiviral efficacy and safety of these inhibitors against SARS-CoV-2 and other coronaviruses.
  • To assess the anti-inflammatory properties of the identified compounds.

Main Methods:

  • Identification of peptidomimetic α-ketoamide compounds (14a and 14b) as dual CTSL and CAPN1 inhibitors.
  • X-ray crystallography to elucidate the binding mechanism of compounds with CTSL and CAPN1.
  • In vitro antiviral assays against SARS-CoV-2 and its variants, and HCoV-OC43.
  • In vivo studies in mouse models to assess pharmacokinetic properties, safety, antiviral efficacy, and anti-inflammatory effects.

Main Results:

  • Compounds 14a and 14b potently inhibited CTSL and CAPN1, with X-ray structures confirming covalent binding.
  • Both compounds demonstrated broad-spectrum in vitro antiviral activity, including low nanomolar potency against SARS-CoV-2 and its variants (VOCs).
  • In vivo studies showed favorable oral pharmacokinetics, good safety profiles, potent antiviral activity against SARS-CoV-2 XBB 1.16 and HCoV-OC43, and significant anti-inflammatory effects.

Conclusions:

  • Compounds 14a and 14b are potent dual inhibitors of CTSL and CAPN1 with broad-spectrum antiviral and anti-inflammatory properties.
  • These compounds represent promising drug candidates for developing pan-coronavirus inhibitors.
  • The findings offer novel insights into host-targeting strategies for managing current and future coronavirus threats.

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