{"id":849291,"date":"2025-05-18T19:12:26","date_gmt":"2025-05-19T00:12:26","guid":{"rendered":"https:\/\/newsycanuse.com\/index.php\/2025\/05\/18\/new-drugs-outperform-paxlovid-a-game-changer-for-covid-and-future-pandemics\/"},"modified":"2025-05-18T19:12:26","modified_gmt":"2025-05-19T00:12:26","slug":"new-drugs-outperform-paxlovid-a-game-changer-for-covid-and-future-pandemics","status":"publish","type":"post","link":"https:\/\/newsycanuse.com\/index.php\/2025\/05\/18\/new-drugs-outperform-paxlovid-a-game-changer-for-covid-and-future-pandemics\/","title":{"rendered":"New Drugs Outperform Paxlovid \u2013 A Game Changer for COVID and Future Pandemics"},"content":{"rendered":"
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\"New<\/a>
Researchers at UC San Francisco and Gladstone Institutes developed new antiviral drug candidates that outperformed Paxlovid against SARS-CoV-2 and MERS in preclinical testing, offering hope for future pandemic preparedness. Despite their promise, funding cuts threaten the advancement of these compounds, which uniquely target viral enzymes without harming human proteins.<\/figcaption><\/figure>\n

The Antiviral Drug Discovery (AViDD) Center at UCSF is pioneering the development of potent drug candidates aimed at preventing future coronavirus pandemics.<\/strong><\/p>\n

Researchers at UC San Francisco<\/a> and the Gladstone Institute<\/a>s have developed new drug candidates that show strong potential against the virus<\/div>\n

A virus is a microscopic infectious agent that can replicate only inside the living cells of an organism. Viruses can infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea. Structurally, viruses consist of genetic material\u2014either DNA or RNA\u2014enclosed in a protective protein coat called a capsid, and sometimes a lipid envelope. They are uniquely distinguished by their simple, acellular organization and mode of reproduction, which involves hijacking the host cell's machinery to produce new virus particles. This process often results in disease in the host organism. Viruses are responsible for a wide range of diseases, including the common cold, influenza, HIV\/AIDS, and COVID-19. Despite their pathogenic nature, viruses also play roles in ecological and evolutionary processes, influencing gene transfer and genetic diversity.<\/div>\n

” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>virus<\/span> responsible for COVID-19<\/div>\n

First identified in 2019 in Wuhan, China, COVID-19, or Coronavirus disease 2019, (which was originally called "2019 novel coronavirus" or 2019-nCoV) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has spread globally, resulting in the 2019\u201322 coronavirus pandemic.<\/div>\n

” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>COVID-19<\/span>, as well as other coronaviruses that could drive future pandemics.<\/p>\n

In preclinical studies, these compounds outperformed Paxlovid in combating both SARS-CoV-2<\/div>\n

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the official name of the virus strain that causes coronavirus disease (COVID-19). Previous to this name being adopted, it was commonly referred to as the 2019 novel coronavirus (2019-nCoV), the Wuhan coronavirus, or the Wuhan virus.<\/div>\n

” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>SARS-CoV-2<\/span> and the Middle East Respiratory Syndrome (MERS) virus, a pathogen known for causing deadly outbreaks around the world.<\/p>\n

\u201cIn three years, we\u2019ve moved as fast as a pharmaceutical company would have, from start to finish, developing drug candidates against a totally new pathogen,\u201d said Charles Craik, PhD, UCSF professor of pharmaceutical chemistry and co-corresponding author of the paper, which appears April 23 in Science Advances<\/div>\n

<em>Science Advances<\/em> is a peer-reviewed scientific journal established by the American Association for the Advancement of Science (AAAS). It serves as an open-access platform featuring high-quality research across the entire spectrum of science and science-related disciplines. Launched in 2015, the journal aims to publish significant, innovative research that advances the frontiers of science and extends the reach of high-impact science to a global audience. "Science Advances" covers a broad range of topics including, but not limited to, biology, physics, chemistry, environmental science, and social sciences, making it a multidisciplinary publication.<\/div>\n

” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>Science Advances<\/span><\/em>.<\/p>\n

\u201cThese compounds could inhibit coronaviruses in general, giving us a head start against the next pandemic,\u201d Craik said. \u201cWe need to get them across the finish line and into clinical trials.\u201d<\/p>\n

The work was funded by a grant from the National Institute of Allergy and Infectious Diseases (NIAID) to prepare for the next coronavirus epidemic \u2013 work that pharmaceutical companies have largely abandoned. But the grant to UCSF has since been terminated, and the group\u2019s antiviral drug candidates face an uncertain future.<\/p>\n

The discovery came out of UCSF\u2019s Antiviral Drug Discovery (AViDD) Center for Pathogens of Pandemic Concern, which funded the work of several hundred scientists at UCSF and beyond. It is one of nine centers that NIAD created in 2022 to bolster the nation\u2019s pandemic preparedness.<\/p>\n

From virtual to real-world drug candidates<\/h4>\n

Three years ago, the UCSF AViDD grant supercharged the efforts of the UCSF Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG). QCRG, which was founded in 2020 by QBI\u2019s director, Nevan Krogan, PhD, brought together 800 scientists from more than 40 institutions across the world.<\/p>\n

From this group, he assembled hundreds of scientists from 43 labs across UCSF, Gladstone Institutes, and a wide range of domestic and international institutions \u2013 including Mount Sinai, Northwestern, MIT<\/div>\n

MIT is an acronym for the Massachusetts Institute of Technology. It is a prestigious private research university in Cambridge, Massachusetts that was founded in 1861. It is organized into five Schools: architecture and planning; engineering; humanities, arts, and social sciences; management; and science. MIT's impact includes many scientific breakthroughs and technological advances. Their stated goal is to make a better world through education, research, and innovation.<\/div>\n

” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>MIT<\/span>, the University of Toronto, the University of Alberta, University College London, Institut Pasteur, and others \u2013 and obtained one of the nine AViDD center grants in the country.<\/p>\n

\u201cCOVID was our wake-up call to apply all our resources and know-how toward new therapies and future pandemic preparedness,\u201d said Krogan, UCSF professor of cellular and molecular pharmacology, co-author of the paper, and a leading expert on the biology of infectious disease. \u201cThe AViDD funding, which is now in peril, was poised to help us produce potent and necessary antivirals in record time.\u201d<\/p>\n

For the project that led to the new SARS-CoV-2 drug candidates, Craik, who had experience designing drugs against HIV, partnered with the UCSF labs of Brian Shoichet, PhD; Adam Renslo, PhD; Kliment Verba, PhD; and Krogan, as well as Melanie Ott, PhD (Gladstone Institutes).<\/p>\n

The group focused on the major protease (MPro), a type of enzyme, or protease, that breaks proteins into smaller pieces like a pair of molecular scissors. SARS-CoV-2 uses MPro to trim viral proteins into usable parts, which the virus then uses to replicate in human cells. Viral proteases have often been the target of attempts to make antiviral drugs, most notably for HIV.<\/p>\n

Shoichet\u2019s molecular docking program<\/a>, a virtual system to test how different molecules interact with proteins, helped the team identify a few dozen molecular structures, out of millions, that mildly blocked MPro \u2013 a starting point for developing real-world drug candidates.<\/p>\n

The Renslo lab then synthesized hundreds of new molecules based on the virtual molecules, which the Craik lab tested against MPro in the laboratory.<\/p>\n

\u201cWe spent 18 months going back and forth with different molecules that fit reasonably well inside of MPro, but were still mediocre at blocking it,\u201d Craik said. \u201cOur progress stalled. Something had to give.\u201d<\/p>\n

Jamming the viral scissors<\/h4>\n

Two of Renslo\u2019s post-doctoral researchers, Gilles DeGotte, PhD, and Luca Lizzadro, PhD, were responsible for designing and then making the new molecules in the lab. They were given a task \u201cthat in the pharmaceutical industry would have been assigned to a much larger team of medicinal chemists,\u201d according to Renslo, who is a co-corresponding author of the paper.<\/p>\n

Lizzadro improved the synthesis (like a recipe) for making the molecules and found a way to make them fit more snugly into the \u201cactive site\u201d of MPro, blocking its ability to cut proteins, like jamming open a pair of scissors.<\/p>\n

DeGotte, meanwhile, used \u201cclick chemistry\u201d to improve the molecules\u2019 fit in MPro even further. This involved introducing a molecular adapter that would make it easier to swap different chemical shapes onto each new drug candidate.<\/p>\n

Tyler Detomasi, PhD, a post-doctoral researcher in the Craik Lab, showed that in two such molecules, named AVI-4516 and AVI-4773, the molecular adapter had, itself, bonded to the MPro active site. These molecules weren\u2019t just a perfect fit for MPro \u2013 they were glued within the jaws of the scissors.<\/p>\n

Fortunately, AVI-4516 and AVI-4773 didn\u2019t block any human proteases, which are important for human health. Verba\u2019s lab generated atomic-scale images of the compounds bound to MPro, helping the team to optimize the fit and prove that they were permanently stuck inside the viral enzyme.<\/p>\n

\u201cThis was our lucky break and gave us some very special molecules,\u201d Craik said. \u201cThey only react when they\u2019re already inside this viral protease, but not to any of our own human proteases, giving us hope that they could have minimal side effects in people.\u201d<\/p>\n

A new generation of effective antivirals<\/h4>\n

With rising confidence that AVI-4516 and AVI-4773 effectively blocked MPro, Ott, a virologist, tested them against live SARS-CoV-2, first in petri dishes and then in mice.<\/p>\n

Ott had tested hundreds of drug candidates against SARS-CoV-2 by this point.<\/p>\n

\u201cIt\u2019s very challenging to fight viruses in general, let alone SARS-CoV-2, but these new compounds were some of the best, if not the best, we had ever seen, in terms of eliminating infection,\u201d said Ott, who is a co-corresponding author of the paper.<\/p>\n

The two drug candidates looked promising as disease therapies. They potently blocked their target; they traveled efficiently through the body, ensuring they reached their target; and at least in mice, they appeared safe.<\/p>\n

In a tantalizing follow-up experiment, a further-optimized version of the molecules effectively blocked variants of SARS-CoV-2 like Delta, as well as MERS, a less prevalent but much more deadly coronavirus.<\/p>\n

The team believes their drug candidates, once shepherded through clinical trials to demonstrate safety in humans, could be kept \u201con the shelf\u201d ready to fight the next pandemic caused by a coronavirus.<\/p>\n

\u201cThese compounds are easy to modify and should be easy to manufacture,\u201d Renslo said. \u201cAViDD enabled us to discover important new counter measures for an important class of viral pathogens. It\u2019s critical that we see this project through to clinical studies to ensure we\u2019re better prepared for the next pandemic.\u201d<\/p>\n

Reference: \u201cStructure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus MPro inhibitors with potent in vivo efficacy\u201d by Tyler C. Detomasi, Gilles Degotte, Sijie Huang, Rahul K. Suryawanshi, Amy Diallo, Luca Lizzadro, Francisco J. Zaptero-Belinch\u00f3n, Taha Y. Taha, Jiapeng Li, Alicia L. Richards, Eric R. Hantz, Zain Alam, Mauricio Montano, Maria McCavitt-Malvido, Rajesh Gumpena, James R. Partridge, Galen J. Correy, Yusuke Matsui, Annemarie F. Charvat, Isabella S. Glenn, Julia Rosecrans, Jezrael L. Revalde, Dashiell Anderson, Judd F. Hultquist, Michelle R. Arkin, R. Jeffrey Neitz, Danielle L. Swaney, Nevan J. Krogan, Brian K. Shoichet, Kliment A. Verba, Melanie Ott, Adam R. Renslo and Charles S. Craik, 23 April 2025, Science Advances<\/i>.
\nDOI: 10.1126\/sciadv.adt7836<\/a><\/p>\n

This work was supported by the National Insitute of Allergy and Infectious Diseases (NIAID) Antiviral Drug Discovery (AViDD) grant U19AI171110, other NIAID contracts (75N93019D00021, 75N93023F00001, HHSN272201800007I), the NIH Division of Intramural research, the Roddenberry Foundation, P. and E. Taft, and Gladstone Institutes.<\/p>\n

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University of California – San Francisco
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Researchers at UC San Francisco and Gladstone Institutes developed new antiviral drug candidates that outperformed Paxlovid against SARS-CoV-2 and MERS in preclinical testing, offering hope for future pandemic preparedness. Despite their promise, funding cuts threaten the advancement of these compounds, which uniquely target viral enzymes without harming human proteins. The Antiviral Drug Discovery (AViDD) Center<\/p>\n","protected":false},"author":1,"featured_media":849292,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[22899,40815],"tags":[9411,21915],"class_list":{"0":"post-849291","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-drugs","8":"category-outperform","9":"tag-drugs","10":"tag-outperform"},"aioseo_notices":[],"_links":{"self":[{"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/posts\/849291","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/comments?post=849291"}],"version-history":[{"count":0,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/posts\/849291\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/media\/849292"}],"wp:attachment":[{"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/media?parent=849291"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/categories?post=849291"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/tags?post=849291"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}