Membrane binding proteins of coronaviruses

J Alsaadi, Entedar A; Jones, Ian M

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.