Type II Transmembrane Serine Protease Inhibitors as Host-based Broad Range Antivirals

Background

Type II transmembrane serine proteases (TTSPs) have been identified as potential therapeutic targets for the treatment of respiratory infections by coronaviruses, MERS and influenza. These enzymes are involved in a key component of viral infection (viral spike protein processing) which enable the virus to enter the host cells.

Researchers have developed ketobenzothiazole containing peptidomimetic protease inhibitors in a previous influenza program. So far, preclinical data demonstrate potent antiviral activity against SARS-CoV-2 infection in vitro as well as in vivo in a prophylactic paradigm.

This host-based, broad range respiratory antiviral class of compound is well positioned as a key preparedness step for potential future pandemics requiring immediate intervention when vaccines are not readily available.

Technology Overview

The overall objective of the research is to develop a prophylactic treatment to address potential future pandemics brought on by respiratory viruses and their variants. This treatment would protect individuals during development of vaccines or therapeutic treatments. With regards to the current pandemic, researchers have developed a host-targeted small molecule that inhibits the activity of a key protease, TMPRSS2, essential to the virus’ entry into the cell. The data shows that the patented compound that has been designed is very potent (nM) and exhibits an extremely high selectivity index of more than a million (selectivity index is a measure of the safety of the drug).

These results were obtained in cells but also in animals infected with the Wuhan strain of SARS-CoV-2 but more importantly with the UK and the south african strains. Because the drug targets the genetically stable host, it is not affected by the potentially higher transmissibility or higher infectivity of the viral variants, a very crucial advantage to current approaches. As mentioned, the molecule is now being developed as a prophylactic; in animal studies a single pre-treatment 1 day before infection and three single daily treatments post-infection were sufficient to protect 100% of the animals that were infected.

The next step in further developing this drug would be to study its administration routes (nasal or by inhalation), to obtain a full toxicology screen and to prepare the IND package leading to clinical trials. A copy of the recently published manuscript summarizing the preclinical data is available at: https://www.biorxiv.org/content/10.1101/2021.05.03.442520v1

Stage of Development

• The compound (N-385) is at the lead stage
• In vivo preclinical POC on Wuhan and in vitro preclinical POC on UK and South African strains in prophylactic paradigm
• Early in vitro PK/ADME data available.
• Formulation and optimal route of administration needs to be investigated (nasal mostly)

Benefits

• Key enzyme for infection of broad range of respiratory viruses (COVID-19, Influenza, SARS, MERS, parainfluenza)
• Host-based mechanism inhibitor: not prone to resistance as compared to virus-based inhibitor
• Small molecule: predictable CMC, reproducible and easily scalable

Applications

• Respiratory viruses pandemic early phases/preparedness: this molecule could be stockpiled and used to protect the health workers on the field until to vaccines would be available.

Opportunity

• Actively looking for a licensing partner to pursue the preclinical development of the lead N-385 toward an IND filing.