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In this article, we analyze four recent articles published in Aug-Sept 2020 on the genetic diversity of SARS-CoV-2 and the potential therapeutic targets against it.
Implications of SARS-CoV-2 genetic diversity and mutations on pathogenicity of the COVID-19 and biomedical interventions (Aug 2020)
This study analysed the implications of the genetic diversity and mutations in SARS-CoV-2 on its virulence diversity and investigated how these factors could affect the successful development and application of antiviral chemotherapy and serodiagnostic test kits, and vaccination.
Researchers from Nigeria analyzed all the suitable and eligible full-text articles published between 31st December 2019 and 31st May 2020. Their search showed that SARS-CoV-2 has persistently undergone significant mutations in various parts of its non-structural proteins (NSPs) especially NSP2 and NSP3, S protein, and RNA-dependent RNA polymerase (RdRp).
In particular, the S protein was found to be the key determinant of evolution, transmission, and virulence of SARS-CoV-2, and could be a potential target for vaccine development. Additionally, RdRp could be a major target in the development of antivirals for the treatment of COVID-19.
Given the critical importance of mutations in the pathogenicity of SARS-CoV-2 and in the development of sero-diagnostics, antivirals, and vaccines, the authors of this study recommended that continuous molecular surveillance of SARS-CoV-2 is much needed, as it would potentially prompt identification of new mutants and their impact on ongoing biomedical interventions and COVID-19 control measures.
Many current antivirals, notably nucleoside analogs (NAs), exert their effect by incorporation into viral genomes and subsequent disruption of viral replication and fidelity. The development of anti-CoV drugs has long been hindered by the capacity of CoVs to proofread and remove mismatched nucleotides during genome replication and transcription.
The RNA genome of single-stranded SARS-CoV-2 has two divisions: two-thirds of its genome is made of 16 non-structural proteins (nsp). The last one-third of the genome encodes structural and accessory proteins.
RNA virus replication typically has a high error rate (or low viral fidelity) that helps the virus exist as diverse populations of genome mutants or “quasispecies”. The downside of it is that while low replicative fidelity allows the RNA viruses to adapt to different replicative environments and selective pressures, it also correlates with an increased chance of error catastrophe leading to viral extinction.
Now, in order to keep evolving and maintain its virulence, the virus tries to achieve a fine balance between quasispecies diversity and replicative fitness (replication competence) - this helps the CoVs and other RNA viruses rapidly develop resistance against the antiviral drugs while maintaining viral replicative fitness.
An additional barrier to the development of NAs as antivirals against CoVs is the presence of proofreading enzymes. Some CoV nsp14 enzymes with their unique 3′ to 5′ exonuclease (ExoN) proofreading function may have been a crucial factor in the expansion and maintenance of such large genomes to ensure replication competence.
The viral proteins considered to be the “core” RTC are the RNA-dependent RNA polymerase (RdRp; nsp12) and the nsp13 helicase. The CoV nsp13 is a helicase that can unwind dsRNA in a 5′ to 3′ direction with the resulting single-stranded RNAs (ssRNAs) probably serving as templates for RNA synthesis by the RdRp. The efficiency of viral RNA synthesis is enhanced when these two proteins - nsp12 and nsp13 interact in a functional RTC.
The nsp14 exoribonuclease activity: The ExoN domain is proposed to correct errors made by the RdRp by removing mismatched nucleotides from the 3′ end of the growing RNA strand.
The ExoN 3′ to 5′ exonuclease activity is a key player in a number of crucial processes in the life cycle of CoV. Antiviral drugs do not directly destroy viruses (unlike antibiotics), they inhibit the viral replication at various stages of the virus life cycle.
The Nsp14 protein plays a number of important roles in viral replication & its ExoN domain could be a potential target for the development of novel antiviral drugs. ExoN is both structurally and functionally conserved across CoVs, which makes it a vulnerable target for anti-CoV strategies. ExoN represents a logical therapeutic target of novel genomics technologies.
Inhibiting ExoN activity by nucleic-acid-based approaches while simultaneously treating with conventional NAs could enhance the effectiveness of the NAs. The NAs can interfere with RNA replication and transcription by targeting RdRp. It will reduce the viral replication fidelity and attenuate the disease. NAs are good antiviral candidates as they demonstrate a relatively high barrier to the emergence of resistance.
A study analyzed 27,977 SARS-CoV-2 sequences from 84 countries obtained throughout the course of the pandemic to track and characterize the evolution of the novel coronavirus since its origination. The authors concluded that SARS-CoV-2 genetic diversity is remarkably low and should not be expected to impede the development of a broadly protective vaccine. The vaccines being developed confer immunity to all viral lineages in the global population.
Coronaviruses have an error-correcting capacity: They have an evolved nonstructural protein 14 (nsp14), which accompanies viral replicases during RNA synthesis and excises misincorporated ribonucleotides in their early stages before they can be extended, thus preventing the initial errors from becoming permanent. This makes their replication error at least 10x lower than that of other RNA viruses. This activity also likely contributes to the low genetic diversity of SARS-CoV-2, which may not impede the development of a broadly protective vaccine, assuring us that the vaccines being developed confer immunity to all viral lineages in the global population.
Surface glycoproteins of coronaviruses: For many viruses, surface glycoproteins contain not only elements required for specific binding of cellular receptors, membrane fusion, and virus entry into the host cell but also epitopes recognized by neutralizing antibodies produced as part of an effective adaptive immune response. Hence, tracking genetic variation in the SARS-CoV-2 surface glycoprotein is of paramount importance for determining the likelihood of vaccine effectiveness or immune escape.
Another study found that neutral evolution, rather than adaptive selection, can explain the rare mutations seen across SARS-CoV-2 genomes. In the immunogenic Spike protein, the D614G mutation has become consensus, yet there is no evidence of mutations affecting binding to the ACE2 receptor. The study suggested that, to date, the limited diversity seen in SARS-CoV-2 should not preclude a single vaccine from providing global protection.
The authors seem to be cautiously optimistic that viral diversity should not be an obstacle for the development of a broadly protective SARS-CoV-2 vaccine, and that vaccines in current development should elicit responses that are reactive against currently circulating variants of SARS-CoV-2.