CoVs are a class of genetic diverse viruses found in a wide range of host species, including birds and mammals. Many CoVs cause intestinal and respiratory infections in animals and in humans. CoV came into the spotlight in 2002–2003, when clusters of ‘atypical pneumonia’ were first reported in Guangdong Province, subsequently spreading to Hong Kong. Researchers in Hong Kong isolated a novel CoV virus (SARS-CoV) and the disease was later renamed severe acute respiratory syndrome (SARS). Because of international travel, the virus spread from Hong Kong to the rest of the world and more than 8000 people in 26 countries became infected, with a case fatality rate of approximately 10%
SARS posed a serious public health threat to the world at that time, with a significant negative impact on the economy in affected areas. Subsequent studies found that SARS-CoV originated from bats and interspecies transmission to humans took place via an intermediate host: Himalayan palm civets (Paguma larvata) or raccoon dogs (Nyctereutes procyonoides).Another well-known CoV of animal origin is Middle East respiratory syndrome coronavirus (MERS-CoV), which has an even higher case fatality rate, but it is rarely transmitted between humans.
As major natural reservoir species of Alphacoronavirus and Betacoronavirus, bats carry highly diverse SARS-like-CoVs. These bats are distributed in many provinces of China. The genetic diversity of these SARS-like-CoVs and their molecular evolution within their natural host species have been studied intensively. Here, we review the recent but still very limited facts about the current epidemiology of COVID-19 and discuss viral characteristics of 2019-nCoV on the backdrop of our knowledge about the previous epidemic of SARS and MERS.
Potential Drug Targets in S of 2019-nCoV
No approved antiviral agents are available against the current outbreak, but convalescent sera or monoclonal antibodies inhibit SARS-CoV or MERS-CoV in vitro or in animal models. However, sufficient sera and antibodies can hardly be produced during a large outbreak. Moreover, monoclonal antibodies neutralizing SARS-CoV are not (or only poorly) reactive against 2019-nCoV, indicating that the antibody epitopes are highly variable.Inhibitors of the proteases that prime S for fusion also have antiviral activity.
However, since S can use various proteases for priming, more than one inhibitor is required.
More promising are drugs directed against the highly conserved S2 subunit, such as peptides that inhibit membrane fusion. The proof of principle is enfuvirtide, a 20 amino acid peptide that is identical in sequence to a part of the heptad repeat region 2 (HR2) that forms a six helix bundle with heptad repeat region 1 (HR1). The peptide binds to HR1, which saturates the binding site for HR2, thereby preventing the conformational change that catalyzes membrane fusion. Peptides with a similar mode of action have been developed for the S2 subunit of SARS-CoV and MERS-CoV. They inhibit virus entry, reduce formation of plaques in vitro, and had beneficial effects in a mouse model. The most promising peptide is called E1, which binds with high affinity to the HR1 region of S from SARS-CoV.
Sequence comparison between HR1 of S from SARS-CoV and 2019-nCoV shows various amino acid exchanges, but none of them is involved in binding to E1, indicating that E1 could also be effective against 2019-nCoV.
Another potential drug target might be the cellular enzyme(s) that attach fatty acids to a cluster of cysteines in the cytoplasmic tail of S. The fatty acids are required for S to fuse with the host cell and affect virus assembly, similar to what has been described for other spike proteins, such as HA of influenza virus. Enzymes that attach acyl chains to S have not been identified, but cellular proteins are acylated by one or several of the 23 members of the ZDHHC family, which have distinct, only partly overlapping substrate specificities. If only a few of them might acylate S in airway cells of the lung, their blockade might result in suppression of viral replication, while acylation of cellular proteins will not be (or very little) compromised. Although more research is required, targeting acyltransferases might be promising, since the cluster of cysteines is present in S from all CoV genera, regardless of their origin. Acylation might thus be required for a very basic function of S, arguing that even newly emerged CoVs probably will also rely on this modification of S to replicate efficiently
However, since key proteins of the innate immune response are also palmitoylated, acylation inhibitors might be limited if the proteins of the innate immune response are modified by the same enzymes as viral proteins.
Previous studies showed that CoVs genomes display a high degree of plasticity in terms of gene content and recombination. Furthermore, the relatively large CoV genome increases the probabilities for adaptive mutations, with it being relative easy for the spike protein to exploit multiple cellular receptors for virus attachment and entry. These features are likely the cause of this alarming propensity of CoVs for host-species expansion. Unfortunately, China has seen a number of interspecies transmissions by CoV in recent years. Whether this current COVID-19 epidemic ‘frizzles out’ or expands into a full-blown pandemic remains to be seen. It might also be desirable to monitor farm animals and pet cats for infection with 2019-nCoV, since their ACE2 receptor responsible for 2019-nCoV binding differs in only a few amino acids from human ACE2.
Surveillance might prevent the virus establishing itself in another animal species that is in close contact to humans. In addition, in light of the fact that there are multiple species of CoVs circulating in wildlife species and that these animals are constantly interacting with each other, host-species expansion or interspecies transmission of new CoV to humans seems to be inevitable. Major knowledge gaps regarding the emergence of 2019-nCoV remain exists but worldwide scientists are working with unprecedented speed to investigate the virus, rushing to develop targeted therapeutics. Notwithstanding, a global surveillance network involving veterinarians and animal biologists is urgently needed to monitor, and possibly to predict, potential sources for the emergence of another highly pathogenic CoV. We propose the concept of ‘One Health’ to facilitate scientific exchange across disciplines, sharing of data, and coordinated efforts in order to prevent future outbreaks.
Reference & Source information: https://www.cell.com/
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