Paxlovid Resistance: Challenges And Opportunities

Healthcare Paxlovid Resistance: Challenges And Opportunities William A. Haseltine Contributor Opinions expressed by Forbes Contributors are their own. Jun 9, 2022, 04:11pm EDT | Share to Facebook Share to Twitter Share to Linkedin We should be focusing on developing combinations of small-molecule antiviral drugs to treat and .

. . [+] prevent Covid-19 AFP via Getty Images We find ourselves in a challenging scenario with the current state of the pandemic.

While proving to be effective at reducing hospitalizations, and severe disease, our best vaccines have failed to protect against infection. Tolerance for public health measures is waning or even nonexistent around the world. So how might protect ourselves against this ever-evolving virus? Paxlovid has been our first line of defense in treating breakthrough Covid-19 infections that occur despite vaccination.

Public health officials have attributed lower hospitalization rates in the most recent surge to the use of Paxlovid. The seven-day average of new Covid hospitalizations is approximately 28,000 this week, down from nearly 160,000. However, two recent preprin t studies demonstrate evidence of potential Paxlovid resistance.

These findings present both challenges and opportunities for the future of the pandemic. Paxlovid combines nirmatrelvir, an inhibitor of the SARS-CoV-2 main protease (MPro, also known as 3CL or nsp5), and ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor. Two recent preprint studies in which SARS-CoV-2 was passaged in cells exposed in culture to nirmatrelvir documented the selection of a combination of two and three amino acid substitutions in the main protein protease of SARS-CoV-2 that confer resistance to the nirmatrelvir.

Three substitutions were identified: L50F (in which leucine at position 50 is substituted by phenylalanine), E166A or E166V (in which glutamic acid at position 166 is substituted by alanine or valine) and L167F (in which leucine at position 167 is substituted by phenylalanine). In the study by Jochmans and collaborators , E166A and L167F individually provided low-level resistance (10- and 4-fold) in a biochemical assay, while the triple mutant L50F+E166A+L167F resulted in the highest levels of resistance (72-fold). All substitutions were associated with a significant loss of protease activity, suggesting a reduction in viral fitness.

Consistently, in structural biology analyses, the different substitutions reduced the number of interactions between the inhibitor and the enzyme. In the study by Zhou and collaborators , L50F+E166V provided up to 80-fold resistance, with resistance being conferred by E166V (the double mutant L50F+A173V showed no-to-little resistance) in reverse genetic studies in a homologous cell culture system. Moreover, engineered double mutants showed high fitness in transfection and passage cultures with infectivity titers comparable to those of the original virus.

The fitness cost of single substitutions E166V and A173V was compensated by L50F. In molecular dynamics simulations, E166V and L50F+166V weakened while L50F improved nirmatrelvir binding. MORE FOR YOU CDC: Salmonella Outbreak Has Left 279 Ill, 26 Hospitalized In 29 States Canadians End Up In ICU After Attending ‘Covid Party’ White House Mandates Pfizer Vaccines for Millions of Citizens .

. . Before the FDA Clinical or Safety Reviews Have Been Made Public Both studies are consistent in that the triple mutant L50F+E166A+L167F displays a similar fold increase in resistance of 72-fold relative to the unmutated virus than the double mutant L50F+E166V.

Jochams and collaborators also describe that the appearance of the double mutant L50F+E166A preceded that of the triple mutant L50F+E166A+L167F. Although it is often the case that the resistance mutation(s) carry a viral fitness cost which renders it unlikely for the mutation to spread across the population, the two publications differ in their findings on the fitness phenotype of the variants, which warrants further study. Presently, the only treatment alternatives we have for Paxlovid are Remdesivir and Monoclonal Antibodies.

We have learned that SARS-CoV-2 has developed resistance to Remdesivir and the Omicron variants have developed resistance to most monoclonal antibodies treatments with the exception of Sotrovimab. However, as the virus continues to evolve we can expect that it will develop resistance to Sotrovimab in the near future. These observations suggest that the way forward is to take a lesson from HIV research , another virus that we have failed to produce an infection-blocking vaccine.

We should be focusing on developing combinations of small-molecule antiviral drugs that have proved effective at preventing and treating HIV. The goal of the biotechnology and pharmaceutical industries should be to develop an array of highly potent and specific drugs, each of which targets a different function of the virus. This will require accelerated research and global collaboration that not only breaks down geographic borders but also the silos that exist between academia and the pharmaceutical biotechnology industry.

It will require similar levels of investment and resources that we saw used by The National Institutes of Health for an HIV/AIDS research budget, approximately $2-3 billion a year. With this plan in place, we can hope to have highly effective drugs that both treat and prevent SARS-CoV-2 and put an end to repeated assaults of this pandemic. Follow me on Twitter or LinkedIn .

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