Coronaviruses (CoVs) infect many species causing a variety of diseases with a range of severities. Their members include zoonotic viruses with pandemic potential where therapeutic options are currently limited. Despite this diversity CoVs share some common features including the production, in infected cells, of elaborate membrane structures. Membranes represent both an obstacle and aid to CoV replication – and in consequence – virus-encoded structural and nonstructural proteins have membrane-binding properties. The structural proteins encounter cellular membranes at both entry and exit of the virus while the nonstructural proteins reorganize cellular membranes to benefit virus replication. Here, the role of each protein in membrane binding is described to provide a comprehensive picture of their role in the CoV replication cycle.
CoV membranes as antiviral targets
As CoVs cause such extensive membrane perturbation and as there is an acknowledged lack of available antiviral compounds to combat CoV-induced disease, it is not surprising that membrane rearrangement has been considered as a target for the development of inhibitors that could act as antivirals, along with the more classical targets of the polymerase and proteases [114]. Peptide therapeutics are promising antagonists in this regard as they compete directly for membrane binding or inhibit the conformational mechanisms involved and several peptides have been demonstrated to target various steps in the CoV replication cycle. A HR2 competitive peptide blocked the fusion mechanism of MERS-CoV and prevented virus entry when measured using a pseudotype assay [115] and a more complex 5 helix bundle, designed as a mimic of the final S fusion intermediate, was also active when measured similarly [116]. SARS-CoV has been inhibited similarly [117]. As membrane microdomains are implicated in CoV membrane interaction, drugs that alter microdomain composition, particularly the level of cholesterol present, have been shown to have an effect on some CoVs [118,119]. More general still is the use of drugs which alter intracellular vesicle pH and so inhibit the entry or exit of enveloped viruses, including CoVs [114,120]. Vaccines and passive immunotherapy options have also targeted crucial CoV–membrane interactions. The predominant antibody response to S is to the S1 domain which has been shown to be a successful vaccine candidate [121,122] but the binding of antibodies directed here is subject to antigenic drift and may not be effective for all serotypes. The S2 domain by contrast is generally immunologically silent. Rare antibodies that do target S2 in the stem of S and inhibiting the fusion mechanism, are broadly reactive and so relatively impervious to serotype change [123]. The use of such broadly reactive monoclonal antibodies as therapies may be particularly suitable for the treatment of serious but sporadic CoV infections where general vaccination of the target population is not warranted or is impractical.
Future perspective
With their large, adaptable genomes and their extensive distribution in the biosphere, CoVs will certainly feature in future zoonotic outbreaks; SARS and MERS will not be the last. While vaccination remains the cornerstone of control for viral diseases, it is not quick, a new vaccine may take 15 years to develop and it is very virus specific, a MERS vaccine will not protect against SARS and vice versa. Similarly, antiviral drugs targeting the main enzyme functions of the virus risk being ineffective as a result of sequence variation in the target genes. Targeting the common physiological features of CoV replication; however, offers the possibility of developing panCoV treatments that focus on what is common to this family of viruses rather that what is distinct. There are obvious problems, viral stages that are so closely associated with host biology that toxicity would be expected, but there is also sufficient novelty, nsp-based membrane remodeling, for example, that clear targets for intervention exist. Such a strategy could offer the possibility for the development of panCoV agents of the future. More immediately, as membrane remodeling by CoVs is fundamental to immune evasion, targeting the proteins responsible for the remodeling could reveal the infection to the host immune system much sooner than would otherwise be the case and lead to the curtailment of the infection at a much earlier time, before extensive collateral damage is done. Together, a further understanding of the role of virus proteins in membrane interaction and remodeling, directly and via interaction with host factors, is likely to increase the underpinning data that lead to an increase in the therapeutic options for the control of CoV infections in the future.
Reference & Source information: https://www.futuremedicine.com/
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