Computationally prioritized drugs inhibit SARS-CoV-2 infection and syncytia formation.

Publisher: Oxford University Press Country of Publication: England NLM ID: 100912837 Publication Model: Print Cited Medium: Internet ISSN: 1477-4054 (Electronic) Linking ISSN: 14675463 NLM ISO Abbreviation: Brief Bioinform Subsets: MEDLINE

Publication: Oxford : Oxford University Press
Original Publication: London ; Birmingham, AL : H. Stewart Publications, [2000-

COVID-19*/metabolism ; Giant Cells*/metabolism ; Giant Cells*/virology ; COVID-19 Drug Treatment*; Antiviral Agents/*pharmacology ; Pyrimidines/*pharmacology ; SARS-CoV-2/*metabolism ; Staurosporine/*analogs & derivatives; A549 Cells ; Computational Biology ; Drug Evaluation, Preclinical ; Drug Repositioning ; Humans ; Staurosporine/pharmacology

The pharmacological arsenal against the COVID-19 pandemic is largely based on generic anti-inflammatory strategies or poorly scalable solutions. Moreover, as the ongoing vaccination campaign is rolling slower than wished, affordable and effective therapeutics are needed. To this end, there is increasing attention toward computational methods for drug repositioning and de novo drug design. Here, multiple data-driven computational approaches are systematically integrated to perform a virtual screening and prioritize candidate drugs for the treatment of COVID-19. From the list of prioritized drugs, a subset of representative candidates to test in human cells is selected. Two compounds, 7-hydroxystaurosporine and bafetinib, show synergistic antiviral effects in vitro and strongly inhibit viral-induced syncytia formation. Moreover, since existing drug repositioning methods provide limited usable information for de novo drug design, the relevant chemical substructures of the identified drugs are extracted to provide a chemical vocabulary that may help to design new effective drugs.
(© The Author(s) 2021. Published by Oxford University Press.)

IDCases. 2020 Jun 06;21:e00864. (PMID: 32566483)
Drug Dev Res. 2021 Jun;82(4):474-493. (PMID: 33251593)
J Cheminform. 2013 Jun 22;5(1):30. (PMID: 23800010)
Infect Genet Evol. 2020 Dec;86:104610. (PMID: 33130005)
Cell. 2020 May 28;181(5):1036-1045.e9. (PMID: 32416070)
Arch Med Res. 2020 Oct;51(7):741-742. (PMID: 32546446)
BMC Bioinformatics. 2008 Oct 29;9:461. (PMID: 18959772)
Nucleic Acids Res. 2016 Jan 4;44(D1):D1202-13. (PMID: 26400175)
Sci Rep. 2021 Jun 10;11(1):12310. (PMID: 34112877)
Genome Res. 2011 Dec;21(12):2213-23. (PMID: 21903743)
Drug Des Devel Ther. 2020 Nov 18;14:5045-5058. (PMID: 33239864)
Nucleic Acids Res. 2015 Jan;43(Database issue):D921-7. (PMID: 25313160)
Gigascience. 2020 May 1;9(5):. (PMID: 32449777)
Toxicol Sci. 2007 Jul;98(1):240-8. (PMID: 17449896)
EBioMedicine. 2020 Nov;61:103104. (PMID: 33158808)
Nat Protoc. 2009;4(8):1184-91. (PMID: 19617889)
Nat Commun. 2018 Jul 12;9(1):2691. (PMID: 30002366)
Cureus. 2020 Sep 16;12(9):e10480. (PMID: 32953365)
Methods. 2021 Aug 27;:. (PMID: 34455072)
Science. 2020 Nov 13;370(6518):856-860. (PMID: 33082293)
Sci Rep. 2016 May 09;6:25694. (PMID: 27157787)
Brief Bioinform. 2021 Mar 22;22(2):726-741. (PMID: 33147623)
Front Cell Dev Biol. 2020 Oct 06;8:545089. (PMID: 33123533)
Curr Opin Investig Drugs. 2010 Dec;11(12):1450-65. (PMID: 21154127)
Pharm Res. 2020 Aug 10;37(9):167. (PMID: 32778962)
Mol Inform. 2021 Jan;40(1):e2000113. (PMID: 33405340)
Leukemia. 2001 Jan;15(1):1-9. (PMID: 11243375)
J Biomol Struct Dyn. 2021 Oct;39(16):6195-6217. (PMID: 32686993)
Cell Discov. 2020 Oct 29;6(1):77. (PMID: 33298897)
Bioinformatics. 2004 Feb 12;20(3):307-15. (PMID: 14960456)
Genome Biol. 2014;15(12):550. (PMID: 25516281)
Nucleic Acids Res. 2003 Feb 15;31(4):e15. (PMID: 12582260)
Blood. 2006 Mar 15;107(6):2517-24. (PMID: 16293603)
Bioinformatics. 2016 Jan 15;32(2):235-41. (PMID: 26415724)
Science. 2021 Aug 20;373(6557):931-936. (PMID: 34285133)
Front Pharmacol. 2020 Aug 06;11:1196. (PMID: 32848795)
Nature. 2020 Sep;585(7825):357-362. (PMID: 32939066)
Monaldi Arch Chest Dis. 2020 May 19;90(2):. (PMID: 32425013)
J Gen Virol. 2018 May;99(5):619-630. (PMID: 29557770)
EMBO J. 2021 Aug 16;40(16):e107821. (PMID: 34159616)
J Cheminform. 2015 May 20;7:20. (PMID: 26052348)
Sci Rep. 2021 Mar 29;11(1):7052. (PMID: 33782412)
Nat Rev Drug Discov. 2020 May;19(5):305-306. (PMID: 32273591)
Nature. 2021 Jun;594(7861):88-93. (PMID: 33827113)
Lancet Glob Health. 2020 Dec;8(12):e1453-e1454. (PMID: 33188730)
Arch Virol. 2020 Aug;165(8):1729-1737. (PMID: 32514689)
Brief Bioinform. 2018 Sep 28;19(5):878-892. (PMID: 28334136)
Cell. 2020 Aug 6;182(3):685-712.e19. (PMID: 32645325)
Stat Appl Genet Mol Biol. 2015 Jun;14(3):311-6. (PMID: 25968440)
BMC Genomics. 2007 Oct 25;8:387. (PMID: 17961223)
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D668-72. (PMID: 16381955)
Genome Biol. 2010;11(10):R106. (PMID: 20979621)
Naunyn Schmiedebergs Arch Pharmacol. 2020 Jul;393(7):1137-1152. (PMID: 32430617)
J Med Chem. 2015 Mar 12;58(5):2091-113. (PMID: 25634295)
Biosaf Health. 2021 Apr;3(2):87-91. (PMID: 33585808)
Nucleic Acids Res. 2021 Jan 8;49(D1):D1302-D1310. (PMID: 33196847)
Biomed J. 2021 Mar;44(1):7-17. (PMID: 33589377)
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517)
Clin Cancer Res. 2005 Jun 15;11(12):4444-50. (PMID: 15958629)
J Med Chem. 2013 Sep 12;56(17):6560-72. (PMID: 23688234)
Pediatr Allergy Immunol. 2020 Jul;31(5):454-470. (PMID: 32359201)
Bioinformatics. 2018 Jun 15;34(12):2136-2138. (PMID: 29425308)
J Infect Public Health. 2020 Sep;13(9):1187-1195. (PMID: 32773212)
Clin Epidemiol Glob Health. 2021 Jan-Mar;9:90-98. (PMID: 33521390)
J Clin Virol. 2020 Jun;127:104362. (PMID: 32305883)
PLoS Biol. 2007 Jan;5(1):e8. (PMID: 17214507)
Sci Rep. 2020 Oct 6;10(1):16577. (PMID: 33024223)
Signal Transduct Target Ther. 2021 Mar 27;6(1):134. (PMID: 33774649)
Immunity. 2020 May 19;52(5):731-733. (PMID: 32325025)
Placenta. 2012 Nov;33(11):927-32. (PMID: 22922069)
Pathog Dis. 2020 Jun 1;78(4):. (PMID: 32667665)
Invest New Drugs. 2000 May;18(2):95-107. (PMID: 10857990)
Bioinformatics. 2020 May 1;36(9):2932-2933. (PMID: 31950985)
J Virol. 2005 Nov;79(21):13800-5. (PMID: 16227300)
J Virol. 2021 Oct 13;95(21):e0097521. (PMID: 34406858)
Nat Commun. 2020 Mar 27;11(1):1620. (PMID: 32221306)
Brief Bioinform. 2021 Mar 22;22(2):1430-1441. (PMID: 33569598)
Crit Care. 2020 Jul 13;24(1):422. (PMID: 32660650)
Cell. 2020 Apr 16;181(2):271-280.e8. (PMID: 32142651)
Nature. 2021 Nov;599(7883):114-119. (PMID: 34488225)
Br J Cancer. 2020 Sep;123(5):694-697. (PMID: 32572174)
Comput Struct Biotechnol J. 2021 Jun 14;19:3573-3579. (PMID: 34194678)
Med Res Rev. 2021 Jan;41(1):5-28. (PMID: 32864815)
Sci Rep. 2019 Nov 14;9(1):16862. (PMID: 31727944)
Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (PMID: 29126136)
Sci Immunol. 2020 Jun 5;5(48):. (PMID: 32503877)
Bioinformatics. 2005 Aug 15;21(16):3439-40. (PMID: 16082012)
Sci Rep. 2020 Aug 4;10(1):13093. (PMID: 32753646)
Nature. 2020 Jul;583(7816):459-468. (PMID: 32353859)
EMBO J. 2020 Dec 1;39(23):e106267. (PMID: 33051876)
Science. 2006 Sep 29;313(5795):1929-35. (PMID: 17008526)
EMBO J. 2021 Feb 1;40(3):e107405. (PMID: 33522642)

0066176 Novo Nordisk Foundation; 814572 Horizon 2020; Academy of Finland; Chan Zuckerberg Initiative; GINOP-2.3.2-15-2016-00037 European Regional Development Fund

Keywords: 7-hydroxystaurosporine; COVID-19; SARS-CoV-2; bafetinib; delta variant; drug design; drug repositioning; kinase inhibitors; syncytia; virtual screening

0 (Antiviral Agents)
0 (Pyrimidines)
7BU5H4V94A (7-hydroxystaurosporine)
H88EPA0A3N (Staurosporine)
NVW4Z03I9B (bafetinib)

Date Created: 20211228 Date Completed: 20220201 Latest Revision: 20221207

20231215

PMC8769897

10.1093/bib/bbab507

34962256