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      In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4

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          Abstract

          The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3 pro) of dengue fever virus carries out all enzymatic activities needed for polyprotein processing and is considered to be amenable to antiviral inhibition by analogy. Virtual screening of 300,000 compounds using Autodock 3 on the GVSS platform was conducted to identify novel inhibitors against the NS2B-NS3 pro. Thirty-six compounds were selected for in vitro assay against NS2B-NS3 pro expressed in Pichia pastoris. Seven novel compounds were identified as inhibitors with IC 50 values of 3.9 ± 0.6–86.7 ± 3.6 μM. Three strong NS2B-NS3 pro inhibitors were further confirmed as competitive inhibitors with K i values of 4.0 ± 0.4, 4.9 ± 0.3, and 3.4 ± 0.1 μM, respectively. Hydrophobic and hydrogen bond interactions between amino acid residues in the NS3 pro active site with inhibition compounds were also identified.

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          Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris

          Thi Nguyen, Hye-Jin Woo, Hee-Kyoung Kang … (2012)
          The 3C-like protease (3CLpro) of severe acute respiratory syndrome associated coronavirus (SARS-CoV) is vital for SARS-CoV replication and is a promising drug target. Recombinant 3CLpro was expressed in Pichia pastoris GS115 as a 42 kDa protein that displayed a K m of 15 ± 2 μM with Dabcyl-KTSAVLQSGFRKME-Edans as substrate. Purified 3CLpro was used for inhibition and kinetic assays with seven flavonoid compounds. The IC50 of six flavonoid compounds were 47–381 μM. Quercetin, epigallocatechin gallate and gallocatechin gallate (GCG) displayed good inhibition toward 3CLpro with IC50 values of 73, 73 and 47 μM, respectively. GCG showed a competitive inhibition pattern with K i value of 25 ± 1.7 μM. In molecular docking experiments, GCG displayed a binding energy of −14 kcal mol−1 to the active site of 3CLpro and the galloyl moiety at 3-OH position was required for 3CLpro inhibition activity. Electronic supplementary material The online version of this article (doi:10.1007/s10529-011-0845-8) contains supplementary material, which is available to authorized users.
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            Structure of Dengue Virus

            Ellen G. Strauss, Richard Kuhn, Wei Zhang … (2002)
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              Structure and anti-dengue virus activity of sulfated polysaccharide from a marine alga.

              Kazuya I P J Hidari, Naonori Takahashi, Masataka Arihara … (2008)
              A sulfated polysaccharide, named fucoidan, from the marine alga Cladosiphon okamuranus is comprised of carbohydrate units containing glucuronic acid and sulfated fucose residues. Here we found this compound potently inhibits dengue virus type 2 (DEN2) infection. Viral infection was inhibited when DEN2, but not other serotypes, was pretreated with fucoidan. A carboxy-reduced fucoidan derivative in which glucuronic acid was converted to glucose did not inhibit viral infection. Elimination of the sulfated function group from fucoidan significantly attenuated the inhibitory activity on DEN2 infection with <1% fucoidan. DEN2 particles bound exclusively to fucoidan, indicating that fucoidan interacts directly with envelope glycoprotein (EGP) on DEN2. Structure-based analysis suggested that Arg323 of DEN2 EGP, which is conformationally proximal to one of the putative heparin binding residues, Lys310, is critical for the interaction with fucoidan. In conclusion, both the sulfated group and glucuronic acid of fucoidan account for the inhibition of DEN2 infection.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 13 December 2013
                Publication date Collection: December 2013
                Volume: 18
                Issue: 12
                Pages: 15600-15612
                Affiliations
                [1 ]Department of Biotechnology and Bioengineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, Korea; E-Mails: nguyenhanh040981@ 123456yahoo.com (T.T.H.N.); mockerysn@ 123456naver.com (S.L.)
                [2 ]Research Institute of Bio Food Industry, The Green Bio Research Complex, Seoul National University, San 967-2 Shin-ri, Pyeongchang-gun, Gangwon-do 232-916, Korea
                [3 ]Research Center for Information Technology Innovation, Academia Sinica, 128, Sec.2, Academia Rd., Nankang, Taipei 11529, Taiwan; E-Mails: hsikai.wang@ 123456twgrid.org (H.-K.W.); hychen@ 123456twgrid.org (H.-Y.C.); Simon.Lin@ 123456cern.ch (S.C.L.)
                [4 ]Genomics Research Center, Academia Sinica, 128, Sec.2, Academia Rd., Nankang, Taipei 11529, Taiwan; E-Mail: ywu@ 123456gate.sinica.edu.tw
                [5 ]Department of Physics, Gangneung-Wonju National University, Gangneung 210-702, Korea; E-Mail: dwkim@ 123456gwnu.ac.kr
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: best6238@ 123456gmail.com ; Tel.: +82-62-530-1844; Fax: +82-62-530-1949.
                Article
                Publisher ID: molecules-18-15600
                DOI: 10.3390/molecules181215600
                PMC ID: 6269914
                PubMed ID: 24352016
                SO-VID: ec800f8c-00d3-464e-bcd6-162e54f5223e
                Copyright © © 2013 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 28 October 2013
                Date revision received : 02 December 2013
                Date accepted : 11 December 2013
                Categories
                Subject: Article

                Keywords: dengue fever,inhibitors,ns2b-ns3 protease,virtual screening
                Data availability:
                Keywords: dengue fever, inhibitors, ns2b-ns3 protease, virtual screening

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