Repurposing Clinical Candidates for Nipah and Hendra Viruses

Area of Science:

• Virology
• Pharmacology
• Drug Discovery

Background:

• Nipah virus (NiV) and Hendra virus (HeV) are bat-borne zoonotic paramyxoviruses causing severe human disease.
• No approved small-molecule therapies exist for these deadly henipaviruses.
• Host-protease-mediated viral entry is a potential therapeutic target, but its clinical feasibility is unclear.

Purpose of the Study:

• To systematically evaluate repurposed clinical-stage molecules for activity against NiV and HeV.
• To prioritize drug candidates using an integrated computational, in vitro, and in vivo framework.
• To assess the translational feasibility of host-directed entry inhibition for henipaviruses.

Main Methods:

• Machine-learning-guided prioritization and selection of cathepsin L inhibitors.
• In vitro antiviral assays against NiV (Malaysia, Bangladesh strains) and HeV.
• Pharmacokinetic, tolerability, and efficacy studies in a Syrian hamster model of NiV infection.

Main Results:

• Several cathepsin L inhibitors demonstrated potent and reproducible in vitro inhibition of NiV and HeV.
• The clinical-stage inhibitor relacatib showed sub-micromolar to nanomolar potency in vitro, outperforming favipiravir.
• Relacatib and pyronaridine did not confer in vivo protection in hamsters, likely due to poor pharmacokinetics (limited exposure, rapid clearance).

Conclusions:

• Host-directed cathepsin L inhibition is a viable in vitro strategy against virulent henipaviruses.
• Pharmacological barriers, specifically limited systemic exposure and rapid clearance, hinder in vivo translation of potent inhibitors.
• This study provides crucial insights for future antiviral development against NiV and HeV, emphasizing the need to address pharmacokinetic challenges.