Diarylheptanoids from <i>Alnus japonica</i> Inhibit Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus

Abstract

The papain-like protease (PL pro ), which controls replication of the severe acute respiratory syndrome coronavirus (SARS-CoV), has been identified as a potential drug target for the treatment of SARS. An intensive hunt for effective anti-SARS drugs has been undertaken by screening for natural product inhibitors that target SARS-CoV PL pro . In this study, diarylheptanoids 1-9 were isolated from Alnus japonica, and the inhibitory activities of these compounds against PL pro were determined. Of the isolated diarylheptanoids, hirsutenone (2) showed the most potent PL pro inhibitory activity, with an inhibitory concentration (IC 50 ) value of 4.1 µM. Structure-activity analysis showed that catechol and α,β-unsaturated carbonyl moiety in the molecule were the key requirement for SARS-CoV cysteine protease inhibition.

Synergistic Inhibitor Binding to the Papain‐Like Protease of Human SARS Coronavirus: Mechanistic and Inhibitor Design Implications

“…[12, 13] Fragments F1 – F8 were repurchased from Sigma. Compound purity has been determined by NMR to be ≥95%.…”

“…[12] Second, several natural products, diarylheptanoids isolated from Alnus Japonica , showed inhibitory activity (4.1 µM IC 50 ) against PLpro. [13] In addition to its primary function of viral peptide cleavage, PLpro has been recognized to be involved in deubiquitination, de-ISGylation, and viral evasion of the innate immune response. [2a, 14] SARS-PLpro is a cysteine protease that contains a zinc-binding motif, a catalytic triad, and an ubiquitin-like N-terminal domain (Figure 1).…”

Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019‐nCoV

“…[40][41][42][43][44][45] However,a few low-nm-range inhibitors have been identified that can be used in combination with other protease-inhibitor therapies to help combat the virus. Many of the inhibitors are in the micromolar range in terms of binding to and inhibiting the two proteases.…”

“…In a FRET-baseda ctivity assay,t he IC 50 value of GC376a gainst recombinant SARS 3CLpro was found to be 4.9 times that against FIPV 3CLpro( 4.35 vs. 0.72 mm,r espectively). Arepresentation of the top CoV protease inhibitors providing ascaffold to perform SAR studies in termsofdesigning novel small-molecule protease inhibitors for 2019-nCoV [40][41][42][43][44][45]49] .3 CLpro-1, the most potent inhibitor,ish ighlighted. Figure 7.…”

Bioactivity and Synthesis of Diarylheptanoids From Alpinia officinarum

“…Diarylheptanoids exhibited antiviral activities against influenza virus [61][62][63][64][65], RSV [44,66], poliovirus [44], measles virus [44], herpes simplex virus type 1 (HSV-1) [44], human immunodeficiency virus (HIV) [67], severe acute respiratory syndrome (SARS) virus [68], and Epstein-Barr virus in relation to carcinogenesis [69]. They are characterized as compounds possessing broad antiviral spectrum against DNA and RNA viruses.…”