Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants

PLoS Pathogens

Volumn 13, Issue 5, 2017, Pages

  Zhang, Wei ^a   Bailey Elkin, Ben A ^b   Knaap, Robert C M ^c   Khare, Baldeep ^b   Dalebout, Tim J ^c   Johnson, Garrett G ^b   van Kasteren, Puck B ^c   McLeish, Nigel J ^b   Gu, Jun ^a   He, Wenguang ^b   Kikkert, Marjolein ^c   Mark, Brian L ^b   Sidhu, Sachdev S ^a  

^a UNIVERSITY OF TORONTO   (Canada)

^b UNIVERSITY OF MANITOBA   (Canada)

^c LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; DEUBIQUITINASE; UBIQUITIN; UBIQUITIN DERIVATIVE; UNCLASSIFIED DRUG; ENZYME INHIBITOR; VIRAL PROTEIN;

ARTICLE; BINDING AFFINITY; CELL CULTURE; CHEMICAL MODIFICATION; CONTROLLED STUDY; CRIMEAN CONGO HEMORRHAGIC FEVER; CRIMEAN-CONGO HEMORRHAGIC FEVER VIRUS; CRYSTALLIZATION; DEISGYLATION; DEUBIQUITINATION; DRUG PROTEIN BINDING; DRUG TARGETING; EC50; GENETIC TRANSFECTION; HUMAN; HUMAN CELL; IC50; MIDDLE EAST RESPIRATORY SYNDROME; MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS; MOLECULAR BIOLOGY; NONHUMAN; PROTEIN PROCESSING; VIRAL GENE DELIVERY SYSTEM; VIRUS INHIBITION; VIRUS REPLICATION; WESTERN BLOTTING; ANTAGONISTS AND INHIBITORS; CHEMISTRY; CORONAVIRUS INFECTION; DRUG EFFECTS; ENZYMOLOGY; GENETICS; METABOLISM; PRECLINICAL STUDY; UBIQUITINATION; VIROLOGY;

ANTIVIRAL AGENTS; CORONAVIRUS INFECTIONS; DRUG EVALUATION, PRECLINICAL; ENZYME INHIBITORS; HEMORRHAGIC FEVER VIRUS, CRIMEAN-CONGO; HEMORRHAGIC FEVER, CRIMEAN; HUMANS; MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS; UBIQUITIN; UBIQUITINATION; VIRAL PROTEINS;

EID: 85020191920     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1006372     Document Type: Article

References (62)

1. Komander D, Rape M, The ubiquitin code. Annual review of biochemistry. 2012;81:203–29. Epub 2012/04/25. doi: 10.1146/annurev-biochem-060310-170328 22524316
2. Yau R, Rape M, The increasing complexity of the ubiquitin code. Nat Cell Biol. 2016;18(6):579–86. doi: 10.1038/ncb3358 27230526
3. Jiang X, Chen ZJ, The role of ubiquitylation in immune defence and pathogen evasion. Nature reviews Immunology. 2012;12(1):35–48. PubMed Central PMCID: PMC3864900.
4. Mielech AM, Chen Y, Mesecar AD, Baker SC, Nidovirus papain-like proteases: multifunctional enzymes with protease, deubiquitinating and deISGylating activities. Virus Res. 2014;194:184–90. PubMed Central PMCID: PMCPMC4125544. doi: 10.1016/j.virusres.2014.01.025 24512893
5. Morales DJ, Lenschow DJ, The antiviral activities of ISG15. Journal of molecular biology. 2013;425(24):4995–5008. PubMed Central PMCID: PMCPMC4090058. doi: 10.1016/j.jmb.2013.09.041 24095857
6. Chenon M, Camborde L, Cheminant S, Jupin I, A viral deubiquitylating enzyme targets viral RNA-dependent RNA polymerase and affects viral infectivity. The EMBO journal. 2012;31(3):741–53. PubMed Central PMCID: PMCPMC3273391. doi: 10.1038/emboj.2011.424 22117220
7. Isaacson MK, Ploegh HL, Ubiquitination, ubiquitin-like modifiers, and deubiquitination in viral infection. Cell host & microbe. 2009;5(6):559–70. Epub 2009/06/17.
8. de Wit E, van Doremalen N, Falzarano D, Munster VJ, SARS and MERS: recent insights into emerging coronaviruses. Nature Reviews Microbiology. 2016;14:523–34. doi: 10.1038/nrmicro.2016.81 27344959
9. Bailey-Elkin BA, Knaap RC, Johnson GG, Dalebout TJ, Ninaber DK, van Kasteren PB, et al. Crystal structure of the Middle East respiratory syndrome coronavirus (MERS-CoV) papain-like protease bound to ubiquitin facilitates targeted disruption of deubiquitinating activity to demonstrate its role in innate immune suppression. The Journal of biological chemistry. 2014;289(50):34667–82. PubMed Central PMCID: PMCPMC4263872. doi: 10.1074/jbc.M114.609644 25320088
10. Mielech AM, Kilianski A, Baez-Santos YM, Mesecar AD, Baker SC, MERS-CoV papain-like protease has deISGylating and deubiquitinating activities. Virology. 2014;450–451:64–70. PubMed Central PMCID: PMCPMC3957432.
11. Clementz MA, Chen Z, Banach BS, Wang Y, Sun L, Ratia K, et al. Deubiquitinating and interferon antagonism activities of coronavirus papain-like proteases. J Virol. 2010;84(9):4619–29. PubMed Central PMCID: PMC2863753. doi: 10.1128/JVI.02406-09 20181693
12. Xing Y, Chen J, Tu J, Zhang B, Chen X, Shi H, et al. The papain-like protease of porcine epidemic diarrhea virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase. The Journal of general virology. 2013;94(Pt 7):1554–67. doi: 10.1099/vir.0.051169-0 23596270
13. Devaraj SG, Wang N, Chen Z, Chen Z, Tseng M, Barretto N, et al. Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. J Biol Chem. 2007;282(44):32208–21. PubMed Central PMCID: PMCPMC2756044. doi: 10.1074/jbc.M704870200 17761676
14. Zheng D, Chen G, Guo B, Cheng G, Tang H, PLP2, a potent deubiquitinase from murine hepatitis virus, strongly inhibits cellular type I interferon production. Cell Res. 2008;18(11):1105–13. doi: 10.1038/cr.2008.294 18957937
15. Baez-Santos YM, St John SE, Mesecar AD, The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiviral Res. 2015;115:21–38. doi: 10.1016/j.antiviral.2014.12.015 25554382
16. Hilgenfeld R, From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design. FEBS J. 2014;281(18):4085–96. doi: 10.1111/febs.12936 25039866
17. Frias-Staheli N, Giannakopoulos NV, Kikkert M, Taylor SL, Bridgen A, Paragas J, et al. Ovarian tumor domain-containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses. Cell Host Microbe. 2007;2(6):404–16. PubMed Central PMCID: PMCPMC2184509. doi: 10.1016/j.chom.2007.09.014 18078692
18. Lei J, Mesters JR, Drosten C, Anemuller S, Ma Q, Hilgenfeld R, Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features. Antiviral research. 2014;109:72–82. doi: 10.1016/j.antiviral.2014.06.011 24992731
19. Ratia K, Saikatendu KS, Santarsiero BD, Barretto N, Baker SC, Stevens RC, et al. Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(15):5717–22. PubMed Central PMCID: PMC1458639. doi: 10.1073/pnas.0510851103 16581910
20. James TW, Frias-Staheli N, Bacik JP, Levingston Macleod JM, Khajehpour M, Garcia-Sastre A, et al. Structural basis for the removal of ubiquitin and interferon-stimulated gene 15 by a viral ovarian tumor domain-containing protease. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(6):2222–7. PubMed Central PMCID: PMCPMC3038750. doi: 10.1073/pnas.1013388108 21245344
21. Akutsu M, Ye Y, Virdee S, Chin JW, Komander D, Molecular basis for ubiquitin and ISG15 cross-reactivity in viral ovarian tumor domains. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(6):2228–33. PubMed Central PMCID: PMCPMC3038727. doi: 10.1073/pnas.1015287108 21266548
22. Calistri A, Munegato D, Carli I, Parolin C, Palu G, The ubiquitin-conjugating system: multiple roles in viral replication and infection. Cells. 2014;3(2):386–417. PubMed Central PMCID: PMCPMC4092849. doi: 10.3390/cells3020386 24805990
23. Heideker J, Wertz IE, DUBs, the regulation of cell identity and disease. Biochem J. 2015;465(1):1–26. doi: 10.1042/BJ20140496 25631680
24. Kemp M, Recent Advances in the Discovery of Deubiquitinating Enzyme Inhibitors. Prog Med Chem. 2016;55:149–92. doi: 10.1016/bs.pmch.2015.10.002 26852935
25. Ernst A, Avvakumov G, Tong J, Fan Y, Zhao Y, Alberts P, et al. A strategy for modulation of enzymes in the ubiquitin system. Science. 2013;339(6119):590–5. Epub 2013/01/05. doi: 10.1126/science.1230161 23287719
26. Zhang W, Wu KP, Sartori MA, Kamadurai HB, Ordureau A, Jiang C, et al. System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes. Molecular cell. 2016;62(1):121–36. doi: 10.1016/j.molcel.2016.02.005 26949039
27. Krissinel E, Henrick K, Inference of macromolecular assemblies from crystalline state. Journal of molecular biology. 2007;372(3):774–97. doi: 10.1016/j.jmb.2007.05.022 17681537
28. Yang X, Chen X, Bian G, Tu J, Xing Y, Wang Y, et al. Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease. J Gen Virol. 2014;95(Pt 3):614–26. doi: 10.1099/vir.0.059014-0 24362959
29. Haagmans BL, van den Brand JM, Raj VS, Volz A, Wohlsein P, Smits SL, et al. An orthopoxvirus-based vaccine reduces virus excretion after MERS-CoV infection in dromedary camels. Science. 2016;351(6268):77–81. doi: 10.1126/science.aad1283 26678878
30. Auger A, Park M, Nitschke F, Minassian LM, Beilhartz GL, Minassian BA, et al. Efficient Delivery of Structurally Diverse Protein Cargo into Mammalian Cells by a Bacterial Toxin. Mol Pharm. 2015;12(8):2962–71. doi: 10.1021/acs.molpharmaceut.5b00233 26103531
31. D'Astolfo DS, Pagliero RJ, Pras A, Karthaus WR, Clevers H, Prasad V, et al. Efficient intracellular delivery of native proteins. Cell. 2015;161(3):674–90. doi: 10.1016/j.cell.2015.03.028 25910214
32. Gaj T, Liu J, Anderson KE, Sirk SJ, Barbas CF, 3rd. Protein delivery using Cys2-His2 zinc-finger domains. ACS Chem Biol. 2014;9(8):1662–7. PubMed Central PMCID: PMCPMC4519095. doi: 10.1021/cb500282g 24936957
33. Uppalapati M, Lee DJ, Mandal K, Li H, Miranda LP, Lowitz J, et al. A Potent d-Protein Antagonist of VEGF-A is Nonimmunogenic, Metabolically Stable, and Longer-Circulating in Vivo. ACS Chem Biol. 2016;11(4):1058–65. doi: 10.1021/acschembio.5b01006 26745345
34. Leung I, Dekel A, Shifman JM, Sidhu SS, Saturation scanning of ubiquitin variants reveals a common hot spot for binding to USP2 and USP21. Proceedings of the National Academy of Sciences of the United States of America. 2016.
35. Arkin MR, Tang Y, Wells JA, Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chemistry & biology. 2014;21(9):1102–14. PubMed Central PMCID: PMCPMC4179228.
36. Inn KS, Lee SH, Rathbun JY, Wong LY, Toth Z, Machida K, et al. Inhibition of RIG-I-mediated signaling by Kaposi's sarcoma-associated herpesvirus-encoded deubiquitinase ORF64. J Virol. 2011;85(20):10899–904. PubMed Central PMCID: PMCPMC3187500. doi: 10.1128/JVI.00690-11 21835791
37. Wang S, Wang K, Li J, Zheng C, Herpes simplex virus 1 ubiquitin-specific protease UL36 inhibits beta interferon production by deubiquitinating TRAF3. J Virol. 2013;87(21):11851–60. PubMed Central PMCID: PMCPMC3807349. doi: 10.1128/JVI.01211-13 23986588
38. Barretto N, Jukneliene D, Ratia K, Chen Z, Mesecar AD, Baker SC, The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. J Virol. 2005;79(24):15189–98. PubMed Central PMCID: PMCPMC1316023. doi: 10.1128/JVI.79.24.15189-15198.2005 16306590
39. Chen Z, Wang Y, Ratia K, Mesecar AD, Wilkinson KD, Baker SC, Proteolytic processing and deubiquitinating activity of papain-like proteases of human coronavirus NL63. J Virol. 2007;81(11):6007–18. PubMed Central PMCID: PMCPMC1900296. doi: 10.1128/JVI.02747-06 17392370
40. Lindner HA, Fotouhi-Ardakani N, Lytvyn V, Lachance P, Sulea T, Menard R, The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. J Virol. 2005;79(24):15199–208. PubMed Central PMCID: PMCPMC1316033. doi: 10.1128/JVI.79.24.15199-15208.2005 16306591
41. Ziebuhr J, Schelle B, Karl N, Minskaia E, Bayer S, Siddell SG, et al. Human coronavirus 229E papain-like proteases have overlapping specificities but distinct functions in viral replication. J Virol. 2007;81(8):3922–32. PubMed Central PMCID: PMCPMC1866161. doi: 10.1128/JVI.02091-06 17251282
42. Bergeron E, Albarino CG, Khristova ML, Nichol ST, Crimean-Congo hemorrhagic fever virus-encoded ovarian tumor protease activity is dispensable for virus RNA polymerase function. J Virol. 2010;84(1):216–26. PubMed Central PMCID: PMCPMC2798392. doi: 10.1128/JVI.01859-09 19864393
43. Lombardi C, Ayach M, Beaurepaire L, Chenon M, Andreani J, Guerois R, et al. A compact viral processing proteinase/ubiquitin hydrolase from the OTU family. PLoS Pathog. 2013;9(8):e1003560. PubMed Central PMCID: PMCPMC3744425. doi: 10.1371/journal.ppat.1003560 23966860
44. Miao X, Recent advances in the development of new transgenic animal technology. Cellular and molecular life sciences: CMLS. 2013;70(5):815–28. doi: 10.1007/s00018-012-1081-7 22833168
45. Agrawal AS, Garron T, Tao X, Peng BH, Wakamiya M, Chan TS, et al. Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease. J Virol. 2015;89(7):3659–70. PubMed Central PMCID: PMCPMC4403411. doi: 10.1128/JVI.03427-14 25589660
46. Pascal KE, Coleman CM, Mujica AO, Kamat V, Badithe A, Fairhurst J, et al. Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(28):8738–43. PubMed Central PMCID: PMCPMC4507189. doi: 10.1073/pnas.1510830112 26124093
47. Zhao J, Li K, Wohlford-Lenane C, Agnihothram SS, Fett C, Zhao J, et al. Rapid generation of a mouse model for Middle East respiratory syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(13):4970–5. PubMed Central PMCID: PMCPMC3977243. doi: 10.1073/pnas.1323279111 24599590
48. Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, et al. Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4. J Infect Dis. 2016;213(5):712–22. PubMed Central PMCID: PMCPMC4747621. doi: 10.1093/infdis/jiv499 26486634
49. Li K, Wohlford-Lenane CL, Channappanavar R, Park JE, Earnest JT, Bair TB, et al. Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice. Proceedings of the National Academy of Sciences of the United States of America. 2017.
50. van Doremalen N, Munster VJ, Animal models of Middle East respiratory syndrome coronavirus infection. Antiviral Res. 2015;122:28–38. PubMed Central PMCID: PMCPMC4561025. doi: 10.1016/j.antiviral.2015.07.005 26192750
51. Cockrell AS, Yount BL, Scobey T, Jensen K, Douglas M, Beall A, et al. A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nat Microbiol. 2016;2:16226. doi: 10.1038/nmicrobiol.2016.226 27892925
52. Lee H, Lei H, Santarsiero BD, Gatuz JL, Cao S, Rice AJ, et al. Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV. ACS Chem Biol. 2015;10(6):1456–65. PubMed Central PMCID: PMCPMC4845099. doi: 10.1021/cb500917m 25746232
53. van Kasteren PB, Bailey-Elkin BA, James TW, Ninaber DK, Beugeling C, Khajehpour M, et al. Deubiquitinase function of arterivirus papain-like protease 2 suppresses the innate immune response in infected host cells. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(9):E838–47. PubMed Central PMCID: PMCPMC3587229. doi: 10.1073/pnas.1218464110 23401522
54. Deng X, StJohn SE, Osswald HL, O'Brien A, Banach BS, Sleeman K, et al. Coronaviruses resistant to a 3C-like protease inhibitor are attenuated for replication and pathogenesis, revealing a low genetic barrier but high fitness cost of resistance. J Virol. 2014;88(20):11886–98. PubMed Central PMCID: PMCPMC4178758. doi: 10.1128/JVI.01528-14 25100843
55. Tonikian R, Zhang Y, Boone C, Sidhu SS, Identifying specificity profiles for peptide recognition modules from phage-displayed peptide libraries. Nature protocols. 2007;2(6):1368–86. Epub 2007/06/05. doi: 10.1038/nprot.2007.151 17545975
56. D'Arcy A, Villard F, Marsh M, An automated microseed matrix-screening method for protein crystallization. Acta Crystallogr D Biol Crystallogr. 2007;63(Pt 4):550–4. doi: 10.1107/S0907444907007652 17372361
57. Ireton GC, Stoddard BL, Microseed matrix screening to improve crystals of yeast cytosine deaminase. Acta Crystallogr D Biol Crystallogr. 2004;60(Pt 3):601–5. doi: 10.1107/S0907444903029664 14993707
58. Georgieva DG, Kuil ME, Oosterkamp TH, Zandbergen HW, Abrahams JP, Heterogeneous nucleation of three-dimensional protein nanocrystals. Acta Crystallogr D Biol Crystallogr. 2007;63(Pt 5):564–70. doi: 10.1107/S0907444907007810 17452781
59. Carlotti F, Bazuine M, Kekarainen T, Seppen J, Pognonec P, Maassen JA, et al. Lentiviral vectors efficiently transduce quiescent mature 3T3-L1 adipocytes. Mol Ther. 2004;9(2):209–17. doi: 10.1016/j.ymthe.2003.11.021 14759805
60. van den Worm SH, Eriksson KK, Zevenhoven JC, Weber F, Zust R, Kuri T, et al. Reverse genetics of SARS-related coronavirus using vaccinia virus-based recombination. PloS one. 2012;7(3):e32857. PubMed Central PMCID: PMC3296753. doi: 10.1371/journal.pone.0032857 22412934
61. Schrodinger, LLC. The PyMOL Molecular Graphics System, Version 1.8. 2015.
62. Chou CY, Lai HY, Chen HY, Cheng SC, Cheng KW, Chou YW, Structural basis for catalysis and ubiquitin recognition by the severe acute respiratory syndrome coronavirus papain-like protease. Acta crystallographica Section D, Biological crystallography. 2014;70(Pt 2):572–81. doi: 10.1107/S1399004713031040 24531491