Newswise — New York, NY (January 31, 2022) – Researchers from the Icahn School of Medicine at Mount Sinai have found that nirmatrelvir, molnupiravir, and remdesivir—COVID-19 antiviral therapeutics that have been approved for emergency use by the U.S. Food and Drug Administration—maintain their in vitro antiviral activity against all SARS-CoV-2 variants of concern, including Omicron. By testing these agents against a panel of SARS-CoV-2 variants in live-virus antiviral assays, their recent study, conducted in collaboration with Pfizer, found that all three of these treatments effectively interrupt the viral life cycle by disrupting the viral machinery necessary for its replication and survival. The study results are currently available on bioRxiv and will be submitted to a peer-reviewed journal.  

The SARS-CoV-2 virus can accumulate changes in its genetic code during replication in host organisms, giving rise to viral variants that continue to propel its global spread. Although many variants have been discovered over the past year, only some, such as Delta and Omicron, have been identified and labeled as variants of concern (VOC) because of increased transmissibility and evasion of natural and vaccine-induced immune responses.

The Omicron variant is characterized by a large number of mutations, with 26 to 32 changes in the spike protein. However, the more recently authorized antiviral therapeutics target other viral proteins, which thus far have accumulated fewer mutations. Nirmatrelvir (the active main protease inhibitor, or Mpro, of PAXLOVID™) targets the Mpro, a protein that is critical for the viral life cycle of SARS CoV-2. Molnupiravir and remdesivir target the viral RNA-dependent RNA polymerase (RdRp)—an enzyme that catalyzes replication of the viral RNA.

“It’s crucial to evaluate the efficacy of antiviral therapeutics that have a potential to play a critical role in the public health response to current and future SARS-CoV-2 variants,” said Kris White, PhD, Assistant Professor of Microbiology at the Icahn School of Medicine at Mount Sinai and senior author of the paper. “Our data confirms that all three of these antiviral treatments effectively interrupt the viral life cycle of wild-type SARS-CoV-2 and all variants of concern we tested in in vitro experiments.”

To evaluate the antiviral therapeutic agents, a team of researchers at Icahn Mount Sinai established live-virus immunofluorescence-based antiviral assays with many relevant variants of SARS-CoV-2, including the novel Omicron variant. Variants were collected from de-identified nasopharyngeal swab specimens as part of the routine SARS-CoV-2 surveillance conducted by the Mount Sinai Pathogen Surveillance Program, the first in New York City to identify the Omicron variant on December 2, 2021. Through the assay they developed, the Mount Sinai research team tested the antiviral treatments against wild-type SARS-CoV-2 and the Alpha, Beta, Delta, and Omicron variants. Dr White’s laboratory uses fluorescent antibodies and advanced microscopy techniques to evaluated viral protein accumulation in infected human cells. They found that all three clinical antivirals prevented in vitro viral protein accumulation for the Omicron variant with the same potency as for the wild-type virus and all other variants tested.

Mount Sinai Health System was fortunate to have access to the Omicron variant through the Mount Sinai Pathogen Surveillance Program early on when the variant first arrived on the scene. Through tireless work and coordination, the Mount Sinai Pathogen Surveillance Program has sequenced, analyzed and cultured viral isolates of the latest Omicron as well as other variants of concern in an extraordinarily fast timeframe. This rapid and collaborative work enabled Dr. White and his team to evaluate the in vitro efficacy of the antiviral agents using authentic, disease-causing viral variants. Their study results confirm that therapeutic strategies targeting viral proteins other than the spike protein show robust in vitro activity against many clinically relevant SARS-CoV-2 variants.

As therapies targeting the SARS-CoV-2 Mpro and RdRp proteins become more widely used, the scientific community will need to closely observe mutation rates within these two viral proteins and monitor whether the deployment of these countermeasures impacts the genetic drift towards resistance against nirmatrelvir, molnupiravir, and remdesivir.

Who: Kris White, PhD, Assistant Professor of Microbiology at Icahn Mount Sinai.
Mount Sinai Pathogen Surveillance Program:
Harm van Bakel, PhD, Assistant Professor, Genetics and Genomic Sciences at Icahn Mount Sinai
Emilia Mia Sordillo, MD, PhD, Associate Professor, Molecular and Cell Based Medicine, at Icahn Mount Sinai.
Viviana Simon, MD, PhD, Professor of Microbiology, Pathology, Molecular and Cell Based Medicine, and Medicine (Infectious Disease) at Icahn Mount Sinai. 

Pfizer provided funding for this study. The Mount Sinai Pathogen Surveillance Program is supported, in part, by institutional funds and the SARS-CoV-2 Assessment of Viral Evolution (SAVE) initiative funded through the National Institute of Allergy and Infectious Disease (NIAID) Centers of Excellence for Influenza Research and Response.

Romel Rosales, PhD; Briana L. McGovern; M. Luis Rodriguez; Devendra K. Rai; Rhonda D. Cardin, PhD; Annaliesa S. Anderson, PhD;  PSP study group1; Emilia Mia Sordillo, MD, PhD; Harm van Bakel, PhD; Viviana Simon, MD, PhD; Adolfo García-Sastre, PhD; Kris M. White, PhD. Nirmatrelvir, Molnupiravir, and Remdesivir maintain potent in vitro activity against the SARS-CoV-2 Omicron variant. bioRxiv, January 19, 2022. 


About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. We advance medicine and health through unrivaled education and translational research and discovery to deliver care that is the safest, highest-quality, most accessible and equitable, and the best value of any health system in the nation. The Health System includes approximately 7,300 primary and specialty care physicians; 13 free-standing joint-venture centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island; and more than 30 affiliated community health centers. The Mount Sinai Hospital is ranked in U.S. News & World Report's "Honor Roll" of the top 20 U.S. hospitals and among the top in the nation by specialty: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Urology, and Rehabilitation. Mount Sinai Kravis Children's Hospital is ranked in U.S. News & World Report’s “Best Children’s Hospitals” among the country’s best in four out of 10 pediatric specialties. New York Eye and Ear Infirmary of Mount Sinai is ranked among the Top 20 nationally for ophthalmology. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and No. 14 in the nation for National Institutes of Health funding. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and top five globally, and Mount Sinai Morningside as top 20 globally, and “The World’s Best Specialized Hospitals” ranks Mount Sinai Heart as No. 1 in New York and No. 4 globally and the Division of Gastroenterology as No. 3 globally, and the Division of Pulmonary Medicine as No. 6 globally.

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Journal Link: bioRxiv