Many people are unaware that, since the release of the Omicron variant, the SARS-CoV-2 coronavirus has been evolving at a breakneck pace, spawning a slew of new variants, subvariants, and even third-generation subvariants with mutations not only in the Spike proteins, but also in the Nucleocapsid proteins, and other structural and non-structural proteins in the viral genome.
In some situations, the number of mutations and degree of divergence of some of these new variants, such as the BA.4 variant and some of the emerging BA.2 and BA.4 subvariants, warrant that they are given their own names and considered as distinct variants, rather than being lumped into the Omicron group.
Many physicians are now discovering that many antiviral drugs, repurposed drugs, supplements, and even herbal based products and phytochemicals that exhibited efficacy in inhibiting virus replication and curtailing viral loads are no longer effective due to the rapid emergence of many of these new sub-variants that are now rapidly spreading and gaining predominance in circulation.
All approved drugs, including remdesivir and paxlovid, as well as mutagenic pharmaceuticals like favipiravir and molnupiravir, supplements like quercetin, herbs like Nigella sativa and its key phytochemical thymoquinone, and other phytochemicals like EGCG (Epigallocatechin Gallate), glycyrrhizin, shikonin, curcumin, resveratrol, hesperidin, rutin, bacailin, etc, to even the grey drug ivermectin are no longer actively effective against inhibiting the new SARS-CoV-2 BA.2 and BA.4 sub-variants.
Fluvoxamine has no antiviral effects on the SARS-CoV-2 virus and aids through an anti-inflammatory mechanism, but it is known to cause arrythmia, which can be fatal in those who are already infected with SARS-CoV-2 because their heart is already being attacked by the virus in many ways!
The major coronavirus protease, also known as the SARS-CoV-2 Mproor 3CLpro, is one of the proteins involved in virus replication and maturation.
Mpro, along with the papain-like protease PLpro, are cysteine proteases (CPs) that digest polyproteins transcribed from viral RNA during SARS-CoV-2 virus replication. As a result, blocking the activity of these enzymes would stop the viral life cycle in its tracks.
Many of the previous antivirals discussed above used a binding method to inhibit these enzymes, hence disrupting the replication process. Paxlovid, for example, an orally accessible Mpro inhibitor that uses a nitrile warhead to covalently bind the catalytic cysteine residue in the active site of the protease, is a combination medication with ritonavir as a booster.
SARS-CoV-2 Mpro is a homodimeric cysteine protease that processes the majority of the ORF1a/b-encoded viral polyproteins pp1a and pp1ab. Mpro inhibition thus prevents the replication and transcription complexes (RTCs) from forming. The protease possesses a specific recognition motif, with (Schechter-Berger notation) a preference for leucine in P2 and a particularly high preference for glutamine in P1.
Missense point mutations can affect protease function, according to previous studies on SARS-CoV-1 Mpro (which is 96 percent similar in amino acid sequence to SARS-CoV-2 Mpro).
Mutants with slightly increased (Ser284, Thr285, Ile286) or slightly or substantially reduced catalytic activity have been found (Gly11, Asn28, Ser139, Phe140, Glu166, Asn214, Arg298). The R298A mutation, which inactivates the protease by destroying the Mpro dimer, has become a tool for studying the protease in its monomeric form.
Since the advent of the major D614 mutation, the SARS-CoV-2 has been changing, and numerous mutations have appeared on the many variants from the Alpha, Beta, Delta, Gamma, Lambda, and Omicron variants, which also affect the Mpro and PLproproteases.
Certain antivirals’ efficacy has been harmed as a result of these modifications.
Many missense mutations in the Mpro region of the ORF1a/b gene are being discovered in the Omicron variant and the newer BA.2 and BA.4 subvariants.
All of these new mutations are leading the Mpro part of the virus to react differently to previous antiviral compounds, rendering them ineffective.
(We can’t say anything about the BA.5 variant because there’s no research or observational data on how these antivirals work against it.)
Experts urge independent and credible researchers to conduct more research on the missense mutations in the Mpro section of the ORF1a/b gene of these new BA.2 and BA.4 subvariants, as well as the efficacy of many approved drugs, supplements, and herbal health supplements currently in use, as the BA.2 and BA.4 subvariants are beginning to become the dominant variants in circulation in various geolocations around the world.
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