Antivirals in the Time of Coronavirus

An Evaluation of Remdesivir and Hydroxychloroquine

Many years ago, efforts to contain HIV resulted in the first widespread successful use of antiviral drugs, including deoxynucleotide analogs such as AZT, able to terminate reverse transcription of viral RNA. The current coronavirus pandemic has spurred extensive efforts to identify effective and safe anti-SARS-CoV-2 drugs. Recent reports have excited interest in Gilead’s remdesivir. Remdesivir’s activity is somewhat analogous to AZT, in that it is a nucleotide analog, but it has a 3-OH group and is not therefore a classical RNA chain terminator. Nevertheless, an analysis in vitro shows that it causes termination of transcription of viral RNA by RNA-dependent RNA polymerase RDRP 3 residues after its incorporation. There are some excellent reports characterizing in vitro activity of remdesivir against SARS-CoV-2 RDRP (1-4).

Remdesivir use has some potential issues. It is not orally bioavailable and must be infused. Treatment duration is a question still to be answered. Cost could be an issue. The SARS-CoV-2 has a 5’-3’ exonuclease which potentially could remove inappropriate nucleotide analogs, but at least in vitro with purified RDRP, this does not appear to happen.

Remdesivir (credit: Ulrich Perrey / Pool via Reuters)

The big question is of course is what is its therapeutic value? The recent excitement has come from two reports. One, in the New England Journal of Medicine, reported results from an uncontrolled compassionate use trial(5). Of 53 patients, 68% showed clinical improvement. More dramatic results were reported during a faculty video discussion at University of Chicago. Out of 113 patients with severe disease treated with remdesivir, most were successfully discharged and only two died. Again, however, this amounts to an uncontrolled trial, although the results are quite encouraging. These results represent preliminary findings from a trial sponsored by Gilead with 2,400 severe disease cases and 1600 moderate disease cases which is comparing treatments of five days duration with those of 10 days duration, so there is no true control group. However, further results are eagerly anticipated.

It appears that at the very least, targeting RDRP will be a fruitful approach. The development of an orally bioavailable version of remdesivir seems important. Since the structure of the RDRP is known, design of more powerful inhibitors should be possible. Finally, processing of the viral polyproteins into their functional forms requires a viral protease, called 3CL, for which it should be possible to design inhibitors. Protease inhibitors have proven highly effective in the cases of HIV and hepatitis C virus and could prove a useful alternative or additional target against SARS-CoV-2. Candidates for 3CL inhibitor lead compounds have already been identified(6).

Hydroxychloroquine has also received some attention, although its benefits are not yet clear, and it has some risky cardiac side effects. Although hydroxychloroquine has some activity in vitro against SAR-CoV-2 as well as other coronaviruses, it does not appear to have anti-coronaviral activity in infected animals. There have been several small studies reported in Covid19 patients. One in France, published online, showed a reduction in viral RNA in patients treated with hydroxychloroquine ± azithromycin.  However, this was not a randomized trial, had small numbers of patients, and had a number of methodological flaws. The other study, a controlled multicenter trial in China with 75 patients treated and 75 in the control arm. No effect was noted on viral RNA levels, but some clinical benefit was observed. A trial in Brazil was halted due to cardiotoxocity. The effects of hydroxychloroquine have been attributed to alteration of the endosomal compartment, affecting viral entry; alteration of glycosylation of ACE2, the spike protein receptor, reducing affinity; and immunomodulation, lowering an overly active inflammatory response. Its usefulness in Covid19 thus remains unsettled.  More recently, a larger but still non-controlled study was reported by the Veterans Administration with 368 patients (hydroxychloroquine alone, n=97; hydroxychloroquine plus azithromycin, n=113; and no hydroxychloroquine, n=158).   No benefit was observed; deaths were higher in the hydroxychloroquine group. The benefit/risk ratio of hydroxychloroquine is still unclear. Novartis is initiating a large clinical trial in the US to determine efficacy that could help answer this question.

  1. Y. Gao et al., Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science, (2020).
  2. C. J. Gordon et al., Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem, (2020).
  3. A. Shannon et al., Remdesivir and SARS-CoV-2: structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites. Antiviral Res, 104793 (2020).
  4. T. P. Sheahan et al., An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med, (2020).
  5. J. Grein et al., Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med, (2020).
  6. Z. Jin et al., Structure of M(pro) from COVID-19 virus and discovery of its inhibitors. Nature, (2020).

 

View All GVN SARS-CoV-2 Perspectives

Dr. Robert Gallo Exclusive Broadcast Interview with Walter Isaacson of Amanpour & Co.

Can an Oral Polio Vaccine Help Stop COVID-19? 

Please see this just released Associated Press article, “Could old vaccines for other germs protect against COVID-19?” with Dr. Robert Gallo (Institute of Human Virology at the University of Maryland School of Medicine) and Dr. Konstantin Chumakov (U.S. Food and Drug Administration), both of the Global Virus Network (GVN).

Also, watch tonight on PBS at 11 pm EDT and subsequently on CNN International an exclusive broadcast interview by Amanpour & Co: Can an oral polio vaccine help stop the coronavirus? Renowned HIV/AIDS biomedical scientist @DrRobertCGallo explains to @WalterIsaacson why he believes it can be used as emergency, short-term protection. @AmanpourCoPBS

UPDATE: Watch full interview between Amanpour & Co.’s Walter Isaacson and Dr. Robert Gallo here.

You can find additional, recent articles on our GVN SARS-CoV-2 page.

Media Contact:

Nora Samaranayake
Public Relations Senior Advisor
Global Virus Network (GVN)
725 West Lombard St.
Baltimore, MD 21201
443-823-0613
[email protected] (email is preferable)

Global Virus Network’s Institute of Human Virology and Italian Scientists Identify Unique Mutations in SARS-CoV-2 Found in Europe and North America

BALTIMORE, MD, April 9, 2020: The Institute of Human Virology (IHV) at the University of Maryland School of Medicine, a Global Virus Network (GVN) Center of Excellence, and scientists from Trieste, Italy announced today the characterization of a novel mutation in the RNA polymerase of certain viral strains of SARS-CoV-2 carried by patients located in Europe and North America. In addition, different patterns of mutations were identified in viral strains corresponding to different geographical areas. The data were obtained by analyzing more than 200 widespread full-length genomic sequences from the National Center for Biotechnology Information (NCBI) and the Global Initiative on Sharing All Influenza Data (GISAID) databases from December 2019 to March 2020.

“We are pleased to collaborate with colleagues in Trieste, and work within the framework of the Global Virus Network, to identify SARS-CoV-2 mutations and their implications in the pandemic, and to advise for therapeutics and vaccine development,” said Robert Gallo, MD, The Homer & Martha Gudelsky Distinguished Professor in Medicine, Co-Founder and Director, Institute of Human Virology (IHV) at the University of Maryland School of Medicine and Co-Founder and Chairman of the International Scientific Leadership Board of the Global Virus Network (GVN).

The findings show that SARS-CoV-2 is quickly evolving and different European, North American and Asian strains may coexist, however, more research is needed to identify the biological significance of these mutations.

“We need to understand the biological and medical significance of the mutations,” said Davide Zella, PhD, Assistant Professor of Biochemistry and Molecular Biology, Institute of Human Virology at the University of Maryland School of Medicine and member, Global Virus Network. “We will continue to collaborate with our Italian colleagues to identify viral mutations in this region.”

“We are excited by these results as they can be applied to improve diagnostic tools to better detect this virus,” said Rudy Ippodrino, PhD, Chief Scientific Officer of Ulisse Biomed, Trieste, Italy.

The data were submitted to, and preprinted by, the Journal of Translational Medicine.

About the Institute of Human Virology

Formed in 1996 as a partnership between the State of Maryland, the City of Baltimore, the University System of Maryland and the University of Maryland Medical System, IHV is an institute of the University of Maryland School of Medicine and is home to some of the most globally-recognized and world-renowned experts in all of virology. The IHV combines the disciplines of basic research, epidemiology and clinical research in a concerted effort to speed the discovery of diagnostics and therapeutics for a wide variety of chronic and deadly viral and immune disorders – most notably, HIV the virus that causes AIDS. For more information, www.ihv.org and follow us on Twitter @IHVmaryland.

About the Global Virus Network (GVN)

The Global Virus Network (GVN) is essential and critical in the preparedness, defense and first research response to emerging, exiting and unidentified viruses that pose a clear and present threat to public health, working in close coordination with established national and international institutions.  It is a coalition comprised of eminent human and animal virologists from 53 Centers of Excellence and 9 Affiliates in 32 countries worldwide, working collaboratively to train the next generation, advance knowledge about how to identify and diagnose pandemic viruses, mitigate and control how such viruses spread and make us sick, as well as develop drugs, vaccines and treatments to combat them.  No single institution in the world has expertise in all viral areas other than the GVN, which brings together the finest medical virologists to leverage their individual expertise and coalesce global teams of specialists on the scientific challenges, issues and problems posed by pandemic viruses. The GVN is a non-profit 501(c)(3) organization. For more information, please visit www.gvn.org. Follow us on Twitter @GlobalVirusNews

 

Media Contact:
Nora Samaranayake, GVN
443-823-0613
[email protected]