MERS-coronavirus: From discovery to intervention

Widagdo, W.; Okba, Nisreen M.A.; Stalin Raj, V.; Haagmans, Bart L.

Due to its limited effective therapeutic window of opportunity, broad spectrum antiviral agents might not be sufficient to treat severe MERS-CoV patients. Several promising CoV specific therapeutic agents have recently been reviewed extensively [27] . These include efforts to develop effective intervention measures aiming to disrupt the interaction of MERS-CoV with its host receptor, dipeptidyl peptidase 4 (DPP4). Although, the crystal structure of DPP4 and the S1 protein of MERS-CoV allowed visualization of the interacting amino acids in both proteins, no antagonists other than adenosine deaminase (ADA) and antibodies that recognize the receptor binding domain (RBD) have been identified so far [28] [29] [30] . Importantly, inhibitors of the enzymatic activity of the DPP4, generally used to treat type 2 diabetes patients, did not block infection of target cells with MERS-CoV [31] . Another potential target for treatment is the S2 protein of MERS-CoV, a subdomain of S protein that mediates fusion of the virus in the endosome. Interaction between heptad region (HR) 1 and 2 within S2 protein is imperative for MERS-CoV entry into its target cell. This interaction can be disrupted using an artificial HR2 homologous peptide, making it a promising entry inhibitor for MERS-CoV [32, 33] . There are also novel drugs aimed at inhibiting virus replication within host cells, targeting the non-structural proteins (nsp) of coronaviruses. Examples are K22, a novel inhibitor of nsp6 [34] and SSYA10-001 that acts on nsp13 [35] . The pocket binding ligand of these compounds is conserved among coronaviruses making them promising pan-coronavirus replication inhibitors.