%A Kandeel,Mahmoud %A Yamamoto,Mizuki %A Park,Byoung Kwon %A Al-Taher,Abdulla %A Watanabe,Aya %A Gohda,Jin %A Kawaguchi,Yasushi %A Oh-hashi,Kentaro %A Kwon,Hyung-Joo %A Inoue,Jun-ichiro %D 2021 %J Frontiers in Pharmacology %C %F %G English %K Coronavirus,MERS-CoV,fusion inhibitors,antivirals,Drug Discovery %Q %R 10.3389/fphar.2021.685161 %W %L %M %P %7 %8 2021-June-02 %9 Original Research %# %! MERS-CoV inhibitor peptides %* %< %T Discovery of New Potent anti-MERS CoV Fusion Inhibitors %U https://www.frontiersin.org/articles/10.3389/fphar.2021.685161 %V 12 %0 JOURNAL ARTICLE %@ 1663-9812 %X Middle East respiratory syndrome coronavirus (MERS-CoV), capable of zoonotic transmission, has been associated with emerging viral pneumonia in humans. In this study, a set of highly potent peptides were designed to prevent MERS-CoV fusion through competition with heptad repeat domain 2 (HR2) at its HR1 binding site. We designed eleven peptides with stronger estimated HR1 binding affinities than the wild-type peptide to prevent viral fusion with the cell membrane. Eight peptides showed strong inhibition of spike-mediated MERS-CoV cell-cell fusion with IC50 values in the nanomolar range (0.25–2.3 µM). Peptides #4–6 inhibited 95–98.3% of MERS-CoV plaque formation. Notably, peptide four showed strong inhibition of MERS-CoV plaques formation with EC50 = 0.302 µM. All peptides demonstrated safe profiles without cytotoxicity up to a concentration of 10 μM, and this cellular safety, combined with their anti-MERS-CoV antiviral activity, indicate all peptides can be regarded as potential promising antiviral agents.