Abstract
SARS-CoV is the causative agent of severe acute respiratory syndrome (SARS). The virally encoded 3C-like protease (3CLPro) has been presumed critical for the viral replication of SARS-CoV in infected host cells. In this study, we screened a natural product library consisting of 720 compounds for inhibitory activity against 3CLPro. Two compounds in the library were found to be inhibitive: tannic acid (IC50 = 3 µM) and 3-isotheaflavin-3-gallate (TF2B) (IC50 = 7 µM). These two compounds belong to a group of natural polyphenols found in tea. We further investigated the 3CLPro-inhibitory activity of extracts from several different types of teas, including green tea, oolong tea, Puer tea and black tea. Our results indicated that extracts from Puer and black tea were more potent than that from green or oolong teas in their inhibitory activities against 3CLPro. Several other known compositions in teas were also evaluated for their activities in inhibiting 3CLPro. We found that caffeine, (—)-epigallocatechin gallte (EGCg), epicatechin (EC), theophylline (TP), catechin (C), epicatechin gallate (ECg) and epigallocatechin (EGC) did not inhibit 3CLPro activity. Only theaflavin-3,3′-digallate (TF3) was found to be a 3CLPro inhibitor. This study has resulted in the identification of new compounds that are effective 3CLPro inhibitors.
Highlights
Severe acute respiratory syndrome (SARS) is caused by a newly discovered coronavirus, SARS coronavirus (SARS-CoV) [1,2]
Our results indicated that tannic acid, TF2B and TF3 are 3C-like protease (3CLPro) inhibitors as revealed by the fluorogenic substrate assay (Fig. 3)
Of the 720 natural products screened in this study, tannic acid (Fig. 4a) and TF2B were identified using the high-performance liquid chromatography (HPLC) proteolytic assay to inhibit 50% of the proteolytic acitivity of 3CLPro at concentrations Ͻ10 M
Summary
Severe acute respiratory syndrome (SARS) is caused by a newly discovered coronavirus, SARS coronavirus (SARS-CoV) [1,2]. SARS-CoV is an enveloped virus containing single-stranded RNA of positive polarity. The genome of SARS-CoV comprises one open reading frame (ORF) encoding two overlapping replicase polyproteins, polyprotein-1a (pp1a, ϳ450 kDa) and poplyprotein-1ab (pp1ab, ϳ750 kDa), responsible for virus replication [7]. Proteolytic processing, especially the processing of replicase polyproteins, is one of the crucial steps in the life cycle of many positive-stranded RNA viruses, including coronaviruses. All coronaviruses encode a paplinelike protease (PLP) and a chymotrypsin-like (3CLPro) protease for proteolytic procession during virus maturation [10]. Studies on other coronaviruses have shown that the PLP protein cleaves at no less than two sites on the pp1a polyprotein and that the 3CLPro protease cleaves at least 11 inter-domain sites on the pp1a and pp1ab polyproteins [7]. We examined crude extracts from various teas and a panel of representative natural products in teas for their inhibitory activities against SARS-3CLPro
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