Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an emerging zoonotic virus considered as one of the major public threat with a total number of 2 298 laboratory-confirmed cases and 811 associated deaths reported by World Health Organization as of January 2019. The transmission of the virus was expected to be from the camels found in Middle Eastern countries via the animal and human interaction. The genome structure provided information about the pathogenicity and associated virulent factors present in the virus. Recent studies suggested that there were limited insight available on the development of novel therapeutic strategies to induce immunity against the virus. The severities of MERS-CoV infection highlight the necessity of effective approaches for the development of various therapeutic remedies. Thus, the present review comprehensively and critically illustrates the recent aspects on the epidemiology of the virus, the structural and functional features of the viral genome, viral entry and transmission, major mechanisms of pathogenesis and associated virulent factors, current animal models, detection methods and novel strategies for the development of vaccines against MERS-CoV. The review further illustrates the molecular and computational virtual screening platforms which provide insights for the identification of putative drug targets and novel lead molecules toward the development of therapeutic remedies.
Diagnostic Approaches
Currently, multiple purified monoclonal antibodies are available in clinical and preclinical studies for the development of antimicrobials (Rockx et al., 2010). Studies suggested that two human antibodies (REGN3048 and REGN3051) are known to bind with MERS-CoV RBD and prevent the interaction of cellular receptor DPP4 with S protein and effectively neutralize MERS-CoV infection (Pascal et al., 2015). The antibodies such as REGN3048 and REGN3051 showed no binding with S protein, thus, employed as effective combination for inhibiting MERS-CoV (Aderem et al., 2011). REGN3048 and REGN3051 co-interact with MERS-CoV RBD, which suggested that these antibodies bind to discrete epitopes as they bind to regions of MERS-CoV S protein that are conserved during the natural evolution of the virus. These two antibodies were blocked entry of the virus into susceptible cell lines and neutralize the infection (Pascal et al., 2015).
The diagnostically relevant variations in the neutralization activity have not been detected in several isolates of MERS-CoV. In order to detect the serological response to a specific type of single MERS-CoV serotype, specific protein based sero-assays are essential to be performed (Muth et al., 2015). The development of potential serological assays demand well delineated human or animal sera and antibodies specific to MERS-CoV (Meyer et al., 2014).
Novel Therapeutic Approaches
The conserved nature of the N protein was used to develop vaccines that can induce an adaptive immune response against these proteins. In a study by Zhao et al. (2016) reported that a vaccine candidate induced airway memory CD4+ T cell response against N-specific epitopes of MERS-CoV. In another study suggested that vaccination with recombinant N-terminal domain (rNTD) triggered greater T-cell response than the mice vaccinated with rRBD. The neutralizing activity was also observed in the sera (Jiaming et al., 2017). Recent study revealed that the combination of fusion inhibitory peptide which targets the protein HR1 domain of MERS-CoV S2 and a neutralizing antibody specific for the S1 protein RBD showed synergistic therapeutic activities against MERS-CoV (Wang et al., 2019). Further, the researchers have developed novel neutralizing nanobodies (Nb) which specifically bind to the RBD of MERS-CoV S protein. The Nb was found to be interacted with the conserved domain of MERS-CoV RBD with high affinity and blocked binding of RBD to the receptor of MERS-CoV (Zhao et al., 2018).
Some immunodominant epitopes within the protein structure may contribute negatively to the neutralization activity of the vaccine. For example, a short region of RBD was able to induce higher titer of IgG when compared to other longer regions (Ma et al., 2014). The negative effects of these epitopes can be surmounted by immunofocusing; mapping of the most neutralizing RBD fragment and eliminating unnecessary fragments. This can help in focusing the immune response to important epitopes (Ma et al., 2014). Pallesen et al. (2017) suggested that the structure-based design of S proteins improved their immunogenicity where the high titers of Nabs were observed against MERS-CoV. The major categories of vaccines developed and tested against various animal models are shown in Table 4.
Therapeutic Screening by Computational Biology
In conclusion, MERS-CoV infection continued to be fatal disease and has emerged as one of the epidemic concern. Irrespective of the various studies conducted to determine the distribution, the exact intermediates remain unidentified. There are various animal models available which provided profound insight in understanding the transmission and pathogenecity of the virus in human. The common pathogenesis mechanisms of the virus such as DPP4, PLpro, accessory proteins like p4a and membrane M protein provided significant insight for the screening of novel drug targets for vaccine development. The detailed understanding of the binding mechanism of various inhibitors toward the structural, non-structural, and accessory proteins of the virus probably provide profound insight for lead development. The integration of genome analysis, proteomics studies, immunoinformatics, and systems biology approaches on various animal models have made the recognition of new targets and lead molecules much easier in than the approaches available during earlier time. By considering MERS-CoV infections as one of the great public threats, there is high demand for undertaking the coronavirus research at the deeper molecular level to understand the mechanism of viral infection, development of advanced and rapid detection methods and futuristic therapeutic strategies to combat MERS-CoV infections.
Reference & Source information: https://www.frontiersin.org/
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