Identifying Allosteric Small-Molecule Binding Sites of Inactive NS2B-NS3 Proteases of Pathogenic Flaviviridae .

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101509722 Publication Model: Electronic Cited Medium: Internet ISSN: 1999-4915 (Electronic) Linking ISSN: 19994915 NLM ISO Abbreviation: Viruses Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Viral Nonstructural Proteins*/metabolism ; Viral Nonstructural Proteins*/chemistry ; Viral Nonstructural Proteins*/genetics ; Antiviral Agents*/pharmacology ; Antiviral Agents*/chemistry ; Allosteric Site*; Binding Sites ; Serine Endopeptidases/metabolism ; Serine Endopeptidases/chemistry ; Serine Endopeptidases/genetics ; Flaviviridae/enzymology ; Flaviviridae/genetics ; Flaviviridae/drug effects ; Humans ; Drug Resistance, Viral/genetics ; Dengue Virus/enzymology ; Dengue Virus/genetics ; Dengue Virus/drug effects ; Protease Inhibitors/pharmacology ; Protease Inhibitors/chemistry ; Protease Inhibitors/metabolism ; Flavivirus/enzymology ; Flavivirus/drug effects ; Flavivirus/genetics ; Viral Proteases ; Nucleoside-Triphosphatase ; DEAD-box RNA Helicases

Dengue, West Nile, Zika, Yellow fever, and Japanese encephalitis viruses persist as significant global health threats. The development of new therapeutic strategies based on inhibiting essential viral enzymes or viral-host protein interactions is problematic due to the fast mutation rate and rapid emergence of drug resistance. This study focuses on the NS2B-NS3 protease as a promising target for antiviral drug development. Promising allosteric binding sites were identified in two conformationally distinct inactive states and characterized for five flaviviruses and four Dengue virus subtypes. Their shapes, druggability, inter-viral similarity, sequence variation, and susceptibility to drug-resistant mutations have been studied. Two identified allosteric inactive state pockets appear to be feasible alternatives to a larger closed pocket near the active site, and they can be targeted with specific drug-like small-molecule inhibitors. Virus-specific sequence and structure implications and the feasibility of multi-viral inhibitors are discussed.

ACS Infect Dis. 2015 Sep 11;1(9):428-34. (PMID: 27617926)
Nat Immunol. 2018 Nov;19(11):1189-1198. (PMID: 30333606)
Viruses. 2022 Jun 30;14(7):. (PMID: 35891424)
Bioorg Chem. 2022 Nov;128:106109. (PMID: 36049322)
Methods Mol Biol. 2017;1607:627-641. (PMID: 28573592)
Front Microbiol. 2022 Mar 03;13:847588. (PMID: 35308381)
Science. 2016 Dec 23;354(6319):1597-1600. (PMID: 27940580)
Nucleic Acids Res. 2015 Jan;43(Database issue):D571-7. (PMID: 25428358)
Science. 2016 Jul 29;353(6298):503-5. (PMID: 27386922)
Biochim Biophys Acta Gen Subj. 2020 Apr;1864(4):129521. (PMID: 31931019)
Int J Mol Sci. 2020 Apr 05;21(7):. (PMID: 32260545)
Trends Biochem Sci. 2017 Jun;42(6):443-456. (PMID: 28318966)
J Chem Inf Model. 2010 Nov 22;50(11):2029-40. (PMID: 20977231)
J Comput Aided Mol Des. 2012 Jun;26(6):675-86. (PMID: 22569591)
Pathogens. 2022 Feb 25;11(3):. (PMID: 35335617)
Nucleic Acids Res. 2017 Jan 4;45(D1):D190-D199. (PMID: 27899635)
Bioorg Chem. 2024 Dec;153:107914. (PMID: 39546935)
J Med Virol. 2022 Oct;94(10):4918-4925. (PMID: 35644833)
Int J Mol Sci. 2024 Apr 16;25(8):. (PMID: 38673962)
PLoS Negl Trop Dis. 2009 Dec 08;3(12):e561. (PMID: 19997625)
Structure. 2018 Apr 3;26(4):555-564.e3. (PMID: 29526431)
Virol Sin. 2013 Dec;28(6):326-36. (PMID: 24242363)
ChemMedChem. 2020 Aug 5;15(15):1439-1452. (PMID: 32501637)
Viruses. 2021 Dec 28;14(1):. (PMID: 35062249)
J Neurovirol. 2003 Apr;9(2):274-83. (PMID: 12707858)
Virus Res. 2023 Jan 15;324:199018. (PMID: 36493993)
J Med Virol. 2022 Feb;94(2):442-453. (PMID: 34636434)
J Biol Chem. 2008 Jun 20;283(25):17270-8. (PMID: 18442976)
Bioorg Med Chem Lett. 2020 Mar 1;30(5):126965. (PMID: 31980339)
ACS Med Chem Lett. 2022 Mar 08;13(4):599-607. (PMID: 35450371)
J Virol. 2008 Jan;82(1):173-83. (PMID: 17942558)
Viruses. 2023 Apr 30;15(5):. (PMID: 37243192)
Front Cell Infect Microbiol. 2020 Oct 02;10:580096. (PMID: 33123500)
Nat Methods. 2015 Feb;12(2):131-3. (PMID: 25506719)
Nucleic Acids Res. 2019 Jan 8;47(D1):D506-D515. (PMID: 30395287)
J Virol. 2010 Mar;84(6):3059-67. (PMID: 20042502)
Viruses. 2022 Jun 05;14(6):. (PMID: 35746697)
Nat Struct Mol Biol. 2006 Apr;13(4):372-3. (PMID: 16532006)
Mol Cell Proteomics. 2005 Jun;4(6):752-61. (PMID: 15757999)
Acc Chem Res. 2016 May 17;49(5):809-15. (PMID: 27110726)
J Virol. 2007 Jun;81(12):6471-81. (PMID: 17526891)
Bioorg Med Chem. 2019 Sep 15;27(18):3963-3978. (PMID: 31351847)
J Virol. 2012 Jan;86(1):438-46. (PMID: 22031935)
Protein Sci. 2007 May;16(5):795-806. (PMID: 17400917)
Nat Microbiol. 2020 Jun;5(6):796-812. (PMID: 32367055)
Arch Pharm (Weinheim). 2024 Sep;357(9):e2400250. (PMID: 38809037)
Nat Commun. 2022 May 26;13(1):2947. (PMID: 35618717)
Microorganisms. 2021 Mar 06;9(3):. (PMID: 33800763)
J Am Chem Soc. 2019 May 1;141(17):6832-6836. (PMID: 31017399)
Enzymes. 2021;49:265-303. (PMID: 34696835)
Antiviral Res. 2010 Sep;87(3):281-94. (PMID: 20452379)
Front Cell Infect Microbiol. 2023 Feb 14;13:1061937. (PMID: 36864886)
PLoS Pathog. 2023 Nov 27;19(11):e1011795. (PMID: 38011215)
Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):11513-11518. (PMID: 30341219)
Antiviral Res. 2020 Mar;175:104707. (PMID: 31953156)
J Biol Chem. 2010 Jun 11;285(24):18817-27. (PMID: 20375022)
Front Immunol. 2022 Jan 28;13:829433. (PMID: 35154151)
Biochimie. 2020 Jul;174:117-125. (PMID: 32335227)

R35 GM131881 United States GM NIGMS NIH HHS; NA Foundation for Armenian Science and Technology: FAST-ADVANCE Armenia; R35GM131881 United States NH NIH HHS

Keywords: Dengue; Japanese encephalitis; NS2B; NS3; Yellow Fever; Zika virus; allosteric druggable pockets; mutation rates; protease inhibitors

0 (Viral Nonstructural Proteins)
0 (Antiviral Agents)
EC 3.4.21.- (Serine Endopeptidases)
0 (NS2B protein, flavivirus)
0 (Protease Inhibitors)
0 (NS3 protein, flavivirus)
EC 3.4.- (Viral Proteases)
EC 3.6.1.15 (Nucleoside-Triphosphatase)
EC 3.6.4.13 (DEAD-box RNA Helicases)

Date Created: 20250125 Date Completed: 20250125 Latest Revision: 20250130

20250130

PMC11769402

10.3390/v17010006

39861795