Macrocyclic Inhibitors of the SARS-CoV-2 / ACE-2 Interaction in COVID-19

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The goal of this proposal is to develop and optimize new drugs able to prevent coronavirus entry into human airway cells. This project is a collaboration between Université de Sherbrooke and Nuchem Therpeutics (Montreal), University of British Columbia (Vancouver) and Collège de Shawinigan. Through the current pandemic, we have to humbly recognize that we were ill-prepared for such outbreak. Its human, economic and strategic impacts are global and will be durable. This pandemic has nevertheless mobilized the scientific community at all levels to better understand the mechanisms involved in SARS-CoV-2 infection and find solutions to manage the disease and its consequences. In terms of treatment options, short-term solutions in the form of repurposed drugs or biologics (e.g., antibodies) could possibly provide much-needed relief. This is an emergency response and every possible drug already on the market or in clinical development is being tested. However these drugs were not optimized for SARS-CoV-2. In the mid-term, vaccination will hopefully provide a means to prevent novel infections and carries hopes for large scale prevention. Thus, there is currently no drug specifically targeting SARS-CoV-2, and little know-how to be implemented in potential future coronavirus epidemics. Ultimately, these efforts are expected to lead to a class of drugs known as entry inhibitors, with the potential to not only cure patients infected by SARS-CoV-2 by stopping the virus from penetrating cells, but also to prevent healthy people from being infected. This proposal exploits novel macrocyclic inhibitors targeting protein-protein interactions between the Spike protein of SARS-CoV-2, and its host receptor, ACE-2. The first step of the project is to computationally design macrocycles that mimic motifs found on two proteins involved in viral entry. The second step is to synthesize them, while the third is to test their ability to block the interaction between the two proteins, and demonstrate their ability to block viral infection in cells.