Frequent mutations in viral genomes
Yet another challenge posed by the viruses is the rapid accumulation of high frequency mutations, as they do not have a full-fledged machinery for replication of their genome.
Accumulation of mutations is compounded when the virus has RNA as the genetic material like the COVID-19 agent. Although there are concerted efforts 24×7 all over the world, to develop COVID-19 vaccine, no one is able to assure the safety and efficacy of the over 100 selected vaccine candidates. Several of them may fail to pass the clinical trials. In the past, efforts to develop vaccines for several viruses, especially RNA viruses like Human Immunodeficiency Virus (HIV), remained elusive.
In some cases, the virus had become almost non-existent by the time the vaccine was available. Several of them may fail at different stages in clinical trials. The high frequency of mutations and evolution of multiple strains of the same virus before we understand the ability of the virus to cause disease and its mode of transmission, among others, could be the major reasons for failure of vaccines.
Options to reduce the damage
Biotechnology has to find quicker solutions to biological problems like COVID-19 by way of designer drugs, rapid protective and curative vaccine(s) and comprehensive use of genome sequence data. Over 7,000 sequences of the SARS-CoV-2 were already analysed and more sequences are being deposited in the global network.
Genome sequence data will help understanding the origin, evolution and mutations (if any) in the strains, besides providing the extent of similarity with similar and other RNA viruses. To design drugs, unique structural and functional target(s) are identified in the contagion or in its interactions with the host. The unique targets being limited for viral diseases, the effort will be to search for more ‘specific targets’ within the major target(s).
Drugs for prophylactic use can target the binding of the spike protein of SARS-CoV-2 to the Angiotensin Converting Enzyme-2 (ACE-2) receptor or the circulating ACE-2 in the blood. Efforts to repurpose or reverse-engineer the drugs also have to test the druggable targets with the known drugs and understand their three-dimensional molecular interaction with the targets in general and specific target(s) in particular.
By simulating the in vivo conditions, potential drug candidates (unique to the virus) and the druggable targets are made to interact in silico using high end software. Observations from such interactions help the scientists to understand and assess the usefulness of known drugs for repurpose. Safety and efficacy will be the major issues both with the repurpose and novel drugs to use them against COVID-19.
The major cysteine like (CL) protease (MPro) (that cleaves a long protein molecule into small protein molecules) encoded by the SARS-CoV-2 genome is one such attractive target. Virus genome encoded protein is first formed as a long protein. This long protein has to be cleaved into smaller functional proteins for virus to complete its life cycle in the host.
If smaller proteins are not formed, virus cannot form new virus particles. Using the three dimensional structure of MPro, along with an a-ketoamide inhibitor a lead compound that inhibits the MPro was developed. The compound is under clinical trials to treat the Covid patients. Blocking the active site of the MPro and stopping its activity will prevent the virus to assemble to form new viruses.
Extensive molecular modeling has also been used to predict the structures of at least 19 proteins that are encoded by SARS-CoV-2 genome or other coronaviruses. Important drug targets like the MPro (3CLPro), spike RNA-dependent RNA polymerase and papain like protease (PLPro) were screened using library of natural compounds and potential drugs acting a certain target were analysed. The lead compounds and targets with further in vitro and in vivo studies of SARS-CoV-2 will provide new strategies for drug repositioning to treat COVID-19 infections.
In addition to 3CLPro which is a cysteine protease, another enzyme indispensable in viral life cycle, a ribose methyltransferase, was also selected as druggable target. After extensive computational analyses that involved calculation of binding energies and molecular dynamic simulations raltegravir, paritaprevir, bictegravir and doutegrair were identified as excellent lead candidates as potential therapeutic drugs.
Glenmark has already initiated phase-3 clinical trials on antiviral favipiravir for COVID-19 patients in India. Drug-repurposing and reverse engineering of generic drugs also are effective strategies for drug discovery. In a more recent strategy designated as systems pharmacology-based network medicine platform, potential drug combinations that work in human protein-protein interaction network are being studied.
Drugs like melantoin, mercaptopurine and sirolimus were validated in related approaches for repurposing. All these strategies not only shorten the time required to discover new drugs but considerably reduce the cost of de novo drug development.
Learning to live with virus during lockdown
As India heads for lockdown 4.0, it is better to understand that the science has moved swiftly in the post-COVID period with new lessons learnt and old ones revisited. What used to take 25 years to develop a vaccine when the world feared about the viral Spanish flu in 1918, we have reached a stage where a vaccine is in the offing in less than a year. In the late 20th century the world stared at HIV infection when there was no vaccine nor potential antivirals.
Now, in the last three months several compounds have been declared as potential drugs for SARS-CoV-2 which are at different stages of testing/usage. The scientists have not pinned hopes on one or two vaccines. Multiple efforts have reached the clinical trials stage, giving rise to the hope that we will have a few vaccines that may serve the world population. Backup plans are also made on robust platforms to release multiple vaccines depending on the strain of virus prevalent in a region. Monoclonal antibodies, plasma therapies and similar approaches also induce confidence that we can suppress SARS-CoV-2.
Science has to advance to a level to impede the mutational frequency of the viruses replicating using host machinery. Until such time, we have to live with COVID-19 like epidemics/pandemics and find alternative solutions to temporarily reduce the damage.
Public health authorities and the medical practitioners have offered suggestions that need to be followed to keep the virus away. Lockdown has helped to increase the awareness on the need of physical distance to prevent the spread of Covid-19 in the community. Now, the public has to remember the lessons from lockdown and find ways to live with COVID-19 until we have a remedy.
As several lockdown regulations are relaxed to save the economy, the public should understand that self-hygiene, family hygiene and maintenance of safe physical distance in public space and at work places are to be practiced religiously to tide over the COVID-19 pandemic, until we have proven preventive or curative measures, made available by scientists.
(Author is the Vice Chancellor of University of Hyderabad)
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