antiviral drugs Archives - Amazing Health Advances

Landmark Discovery May Lead to Safe, Effective Antiviral Drugs Against COVID-19

AHA Publisher — Fri, 09 Apr 2021 07:00:03 +0000

Argonne National Laboratory via News-Medical – The COVID-19 vaccines currently rolling out are providing hope that the spread of the disease can be halted. But infection rates are still high, and for those who contract COVID-19, the search for effective treatments remains important. Researchers examining the atomic structure of SARS-CoV-2, the virus that causes COVID-19, have made a landmark discovery that could contribute critical information to the design of safe and effective antiviral drugs in the fight against the virus. “Understanding enzymes goes hand in hand with understanding their atomic structures -; and the higher resolution the better, because subtle differences can affect the interpretation. We wanted the best data possible, so we went to the APS.” (Natalie Strynadka, University of British Columbia) Using a powerful X-ray beam to study SARS-CoV-2 proteins in crystallized form, a team from the University of British Columbia (UBC) has observed -; for the first time ever -; the virus’s main protease, an important enzyme of the virus, performing its function. This widely pursued antiviral target is a central enzyme that allows the virus to cut up large proteins called polyproteins into smaller functional units, a process necessary for the virus to be replicated and infect other human cells. “What we’ve captured at high resolution is one of the important steps in that process that has never been visualized before in any viral protease of this class,” said Natalie Strynadka, the UBC biochemistry professor who led the research team with colleague Mark Paetzel. The research was published in Nature. The breakthrough was made possible by the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility at DOE’s Argonne National Laboratory. The APS produces X-rays that are roughly a billion times brighter than those used by doctors and dentists, allowing researchers to examine the structure of the coronavirus protease in very fine detail at the atomic level. Data was captured at the General Medical Sciences and Cancer Institutes Structural Biology Facility at beamline 23-ID-B at the APS. The newly uncovered information may be of particular interest to scientists worldwide who are racing to develop antiviral treatments for COVID-19. If the main protease is inhibited by a small molecule drug, the polyproteins won’t be clipped into functional pieces, effectively blocking viral replication and subsequent transmission. “We now have a much better blueprint of these mechanistic structures that will inform making the best inhibitor possible,” Strynadka said. ”Better knowing the structure as we now do helps guide drug research, narrowing the field of potential targets instead of having to screen billions of potential molecules.” Michael Becker, a protein crystallographer with Argonne’s X-ray Science Division, said Strynadka’s research stands out because the team was focused on understanding the mechanism of the protease. “This understanding will improve everyone else’s work in designing drugs,” Becker said. ”Because the more deeply you understand how something works, the better the chance you have of controlling or stopping it.” Remote access capabilities at Argonne made it possible for the researchers in British Columbia to collect data in real time and to manipulate the APS beamline located about 2,200 miles away in Illinois. UBC team members Jaeyong Lee and Liam Worrall shipped crystals of the SARS-CoV-2 main protease preserved in liquid nitrogen from Canada to Argonne. Workers at the APS were on hand to answer questions, ensure the working order of the equipment, and load the samples. “The remote interface is fantastic. It’s almost like being there,” Strynadka said. ”We’re very thankful for the use of the APS. Canada does have a national synchrotron facility, but it currently doesn’t have the same capability as the APS, which is a very high-level facility with micro-focused beams. Understanding enzymes goes hand in hand with understanding their atomic structures -; and the higher resolution the better, because subtle differences can affect the interpretation. We wanted the best data possible, so we went to the APS.” To read the original article click here.

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Coronavirus Makes Changes That Cause Cells Not to Recognize It

AHA Publisher — Wed, 29 Jul 2020 07:00:04 +0000

North Carolina State University via EurekAlert – With an alarm code, we can enter a building without bells going off. It turns out that the SARS coronavirus 2 (SARS-CoV-2) has the same advantage entering cells. It possesses the code to waltz right in. On July 24 in Nature Communications, researchers at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) reported how the coronavirus achieves this. The scientists resolved the structure of an enzyme called nsp16, which the virus produces and then uses to modify its messenger RNA cap, said Yogesh Gupta, PhD, the study lead author from the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio. “It’s a camouflage,” Dr. Gupta said. “Because of the modifications, which fool the cell, the resulting viral messenger RNA is now considered as part of the cell’s own code and not foreign.” Deciphering the 3D structure of nsp16 paves the way for rational design of antiviral drugs for COVID-19 and other emerging coronavirus infections, Dr. Gupta said. The drugs, new small molecules, would inhibit nsp16 from making the modifications. The immune system would then pounce on the invading virus, recognizing it as foreign. “Yogesh’s work discovered the 3D structure of a key enzyme of the COVID-19 virus required for its replication and found a pocket in it that can be targeted to inhibit that enzyme. This is a fundamental advance in our understanding of the virus,” said study coauthor Robert Hromas, MD, professor and dean of the Long School of Medicine. Dr. Gupta is an assistant professor in the Department of Biochemistry and Structural Biology at UT Health San Antonio and is a member of the university’s Greehey Children’s Cancer Research Institute. In lay terms, messenger RNA can be described as a deliverer of genetic code to worksites that produce proteins. To read the original article click here.

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Huge WHO Trial of COVID-19 Therapies Begins

AHA Publisher — Tue, 24 Mar 2020 07:00:21 +0000

Dr. Liji Thomas, MD via News-Medical Net – As the world reels from the devastating impact and the looming threat of the novel coronavirus COVID-19, researchers around the globe are racing to find a cure that will reduce symptom severity and reverse the course of the disease, freeing up more hospital space and making it possible to treat more of the severely affected cases. A large trial In tune with this, the World Health Organization (WHO) has commenced a large trial of four treatments that hold the most significant promise of controlling the coronavirus. This is a trial without precedent, with researchers from multiple locations working in unison to collate as much data on the efficacy of these treatments, even while the pandemic is raging. The study is designed with the greatest simplicity, to include thousands of patients in dozens of countries. It is an intentional plan to enable the most overwhelmed hospitals to take part in the trial to collect the most results possible within the shortest time frame. Recycling Drugs The shortest route to developing effective treatments for the virus is to look at existing drugs, either those that are already approved for other diseases, as well as those that are not yet approved but have been shown to help relieve the disease in animal models of the two previous coronavirus epidemics, namely, severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The hope is to find that one or more of these drugs will slow down or kill the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This would play a significant role in saving many critically ill patients, but would also protect thousands upon thousands of healthcare professionals and other associated workers who put their lives at risk each moment they are in their workplace. Also, effective treatments could also push down the time spent by patients in intensive care, making more beds available for those who need it. The Trial The participants in the trial, called SOLIDARITY, will be any patient who is confirmed to have COVID-19 and fulfills the eligibility criteria as decided by the treating physician. After informed consent procedures are completed, the patient’s details are then entered into a website set up specifically for the trial by the WHO. The physician lists the hospital’s available drugs from the four being studied in the trial, and the website randomizes the patient to either one of these drugs or the local standard care being offered for the infection. This completes the enrolment procedure for the trial. The only remaining details, according to one of WHO’s medical officers, Ana Maria Henao-Restrepo, are the day the patient is hospitalized, the date of discharge, leaving or death, the duration of hospitalization, and the need for oxygen or ventilation during the patient’s stay. Design of the trial The design of the trial is not double-blinded, in that the patients know if they are receiving one of the trialed drugs, and may, therefore, show benefit due to the placebo effect. On the other hand, in this particular situation, the WHO is less concerned about conforming to the highest scientific standards and less about optimizing the efficiency of the process to get results as fast as possible. The trial itself was conceived less than a couple of weeks ago, and the agency is hustling to get the required documents and data management facilities up and running within one more week – which is ‘record time,’ according to Henao-Restrepo. The Advantages The simplicity of the trial design has won the approval of many researchers, who feel that more details about the course of the disease aren’t relevant at this stage of knowledge. Virologist Christian Drosten from Berlin says, for instance, “We don’t really know enough about this disease to be sure what it means when the viral load decreases in the throat.” Meanwhile, others are following WHO’s cue. France, for example, is starting an add-on trial in Europe called Discovery, including 3,200 patients from 7 or more countries, testing the same drugs except for chloroquine. Others could also do the same while modifying the requirements to suit their own research goals as well. For instance, they could add on virology tests, do blood chemistry, or imaging of the lungs. Yet, Henao-Restrepo points out, these are not ‘core requirements’ at this stage, though they might well be of great value in the future. The Candidates The drugs to be tested were shortlisted based on: The chances of success The safest drugs The drugs most likely to be available in sufficient numbers to treat a large number of people if found effective These include: Remdesivir This drug inhibits an important viral enzyme called the RNA-dependent RNA polymerase, which is required for viral replication inside the host cell. First developed to fight viruses such as Ebola, it failed to prove effective when tested in the 2019 Ebola epidemic in the Democratic Republic of the Congo. However, laboratory studies in test tubes and animals show it might be effective in fighting coronaviruses, and anecdotal evidence supports this possibility, with at least two patients who were in a critical state being reported to have turned the corner when given the drug. The drawback is that it has to be given intravenously, it is expensive, and is required in only 15% of patients. Chloroquine and Hydroxychloroquine These antimalarials are included chiefly because of the need to decide whether they are useful or not, based on the interest shown in their use in many countries. They reduce the acidity level within endosomes, which are intracellular compartments that receive material from outside the cell. These can be hijacked by viruses to achieve the same aim, namely, to enter the cell. However, the virus that causes COVID-19 enters via a spike receptor on the cell surface rather than endosomes. While cell culture studies indicate some antiviral activity, high doses are required, carrying the potential for toxicity. Animal studies have not shown benefit either. However, over 20 Chinese studies reporting evidence of benefit with chloroquine in COVID-19 patients have been published – all without supporting data. This makes it difficult to evaluate the claims of efficacy. According to the WHO, “WHO is engaging with Chinese colleagues at the mission in Geneva and have received assurances of improved collaboration; however, no data has been shared regarding the chloroquine studies.” A French study was similarly confusing. Moreover, the diversion of these drugs to treat COVID-19 could lead to a deficit for people who use it for well-established indications like malaria or rheumatoid arthritis. The toxicity of hydroxychloroquine, in particular, is disturbing, because it can, though rarely, cause cardiac injury – a concern when people with heart disease are already at risk for severe COVID-19 symptoms. The guideline issued by the U.S. Society of Critical Care Medicine states that “there is insufficient evidence to issue a recommendation on the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19.” Ritonavir/lopinavir This antiviral combination was first approved for the treatment of HIV and consists of a pair of protease inhibitors. However, it also works with other proteases, including coronaviruses, such as in animal models of the MERS, as well as in human SARS and MERS patients. The results in the latter were not encouraging, and neither was the first human trial studying the effect of this combination in COVID-19. Ritonavir/lopinavir with Interferon-Beta The trial will also look at how the two protease inhibitors act together with the inflammation-regulating interferon-beta, now being tested for the first time in human patients with MERS in Saudi Arabia in a randomized controlled design. The use of interferon-beta in severe COVID-19 could well backfire, feel some experts. Drugs tested in the trial The drugs tested in the trial may soon change based on interim results of lack of efficacy, or evidence of harmful effects. The aim, according to Henao-Restrapo, is simple: “It will be important to get answers quickly, to try to find out what works This article has been modified. To read the original article click here.

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