Hit-to-Lead Development of potent broad-spectrum coronavirus fusion inhibitors

Introduction

The Covid-19 pandemic emphasized the urgent need for efficient broad-spectrum antiviral drugs against potential future coronaviruses (CoV) strains that may cause the next COVID pandemic. A critical stage during infection is the fusion of the viral envelope with the host-cell membrane, which depends on the conserved S2 domain of the viral Spike (S) protein.

Targeting the S2 Domain

Hence, targeting the S2 domain is a promising approach to achieving pan-CoV inhibition. Since MERS- and SARS- S proteins bind to different cell-surface receptors through the rapidly diversifying S1 domain, we reasoned that compounds that inhibit both must target the S2 domain.

High-Throughput Screening

We developed and performed a robust fluorescence-based high-throughput screen of 173,227 unique compounds and classified them based on their ability to inhibit infection of pseudoviruses bearing either MERS or SARS-2 S proteins at single-cell resolution.

Key Findings

To our knowledge, this is the largest screen performed to date. This analysis identified several potent broad-spectrum small molecules that inhibit S protein mediated infection at sub-micromolar concentrations. Moreover, the compounds we discovered obey Lipinski's rule of five, indicating that they can potentially become drugs to prevent viral transmission.

Project Goals

This project aims to develop two of the most promising broad-spectrum CoV small molecule inhibitors to create more clinically ready compounds with up to 100% inhibition activity that could be administered orally to:

1. Reduce hospitalizations
2. Prevent chronic effects
3. Reduce mortality

Technical Focus

The technical work in the project is focused on lead optimization leading towards broad-spectrum antiviral drugs against future outbreaks of bat-borne viruses.

Pre-Commercialization Activities

The project also comprises pre-commercialization activities, where IP protection and commercialization planning are the core activities.

Market Impact

Eventually, we will expect our developed compound(s) to boost the market for antiviral therapies for bat-borne viruses.