Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations

Nature Communications
Mélissanne de WispelaerePriscilla L Yang

Abstract

Targeted protein degradation is a promising drug development paradigm. Here we leverage this strategy to develop a new class of small molecule antivirals that induce proteasomal degradation of viral proteins. Telaprevir, a reversible-covalent inhibitor that binds to the hepatitis C virus (HCV) protease active site is conjugated to ligands that recruit the CRL4CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. An optimized degrader, DGY-08-097, potently inhibits HCV in a cellular infection model, and we demonstrate that protein degradation contributes to its antiviral activity. Finally, we show that this new class of antiviral agents can overcome viral variants that confer resistance to traditional enzymatic inhibitors such as telaprevir. Overall, our work provides proof-of-concept that targeted protein degradation may provide a new paradigm for the development of antivirals with superior resistance profiles.

References

Oct 3, 2003·Journal of Medicinal Chemistry·James SeidlerBrian K Shoichet
Jan 16, 2004·Gastroenterology·Takanobu KatoTakaji Wakita
Mar 25, 2004·Journal of the American Chemical Society·John S SchneeklothCraig M Crews
Feb 16, 2005·Proceedings of the National Academy of Sciences of the United States of America·Kui LiStanley M Lemon
Jun 11, 2005·Science·Brett D LindenbachCharles M Rice
Nov 2, 2006·Genome Biology·Anne E CarpenterDavid M Sabatini
Sep 21, 2007·Journal of Virology·Artur KaulRalf Bartenschlager
Oct 17, 2007·Antimicrobial Agents and Chemotherapy·Yi ZhouChao Lin
Nov 8, 2008·Science·Hsueh-Chi Sherry YenStephen J Elledge
Nov 15, 2008·Methods in Molecular Biology·Brett D Lindenbach
Apr 11, 2009·Nature·Teresa A SoucySteven P Langston
May 1, 2009·The New England Journal of Medicine·Christophe HézodeUNKNOWN PROVE2 Study Team
Sep 30, 2009·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Simone SusserChristoph Sarrazin
Mar 13, 2010·Science·Takumi ItoHiroshi Handa
Apr 8, 2011·Journal of Viral Hepatitis·K MorikawaD Moradpour
Sep 8, 2011·Current Protocols in Pharmacology·Brian SchultzWilliam E Delaney
Jan 19, 2012·Antimicrobial Agents and Chemotherapy·Christoph WelschIris Antes
Apr 13, 2012·PLoS Pathogens·Aaron G SchmidtStephen C Harrison
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang
May 24, 2014·Current Opinion in Virology·Tara L Kieffer, Shelley George
Jan 22, 2015·Nucleic Acids Research·Matthew E RitchieGordon K Smyth
Apr 29, 2015·Journal of Hepatology·Jean-Michel PawlotskyJay H Hoofnagle
Jun 16, 2015·Nature Chemical Biology·Daniel P BondesonCraig M Crews
Nov 26, 2015·Angewandte Chemie·Ashton C LaiCraig M Crews
Jun 9, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kanak RainaKevin G Coleman
Feb 10, 2017·Health Promotion International·UNKNOWN World Health Organization
Apr 19, 2017·Angewandte Chemie·David RemillardJames E Bradner
Apr 25, 2017·Nature Chemical Biology·Taisuke UeharaTakashi Owa
Jun 27, 2017·Cell Chemical Biology·Philipp M Cromm, Craig M Crews
Nov 14, 2017·Cell Chemical Biology·George M BurslemCraig M Crews
Nov 14, 2017·Cell Chemical Biology·Hai-Tsang HuangNathanael S Gray
Dec 19, 2017·Nature Chemical Biology·Calla M OlsonNathanael S Gray
Mar 7, 2018·Nature Chemical Biology·Lara N GechijianJames E Bradner

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Citations

May 16, 2020·International Journal of Molecular Sciences·Stefania BartoloniFilippo Acconcia
May 21, 2020·Future Medicinal Chemistry·Xingui LiuDaohong Zhou
Jun 12, 2020·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Takumi Ito, Hiroshi Handa
Aug 5, 2020·Expert Opinion on Therapeutic Patents·Fenju WeiPeng Zhan
Dec 31, 2019·Signal Transduction and Targeted Therapy·Xiuyun SunYu Rao
May 1, 2020·Cells·Ivana GasicTimothy J Mitchison
Jun 28, 2020·Nature Communications·Nicolas BeryTerry Rabbitts
May 20, 2020·Angewandte Chemie·Laura M LuhPhilipp M Cromm
Nov 9, 2020·European Journal of Medicinal Chemistry·Shenxin ZengZhengrong Shen
Nov 19, 2019·Progress in Biophysics and Molecular Biology·Pooja Gopal, Thomas Dick
Feb 1, 2020·Molecular Cell·Rati VermaRaymond J Deshaies
Feb 8, 2021·Current Opinion in Chemical Biology·Ronen Gabizon, Nir London
Apr 24, 2021·European Journal of Medicinal Chemistry·Patrick D FischerHaribabu Arthanari
May 22, 2021·Future Medicinal Chemistry·Kalyn M RambacherMasaya Yamaguchi
May 25, 2021·Frontiers in Molecular Biosciences·Matylda Anna IzertMaria Wiktoria Górna
Jun 19, 2021·Bioorganic Chemistry·Jayanta DowarahVed Prakash Singh
Jun 28, 2021·Bioorganic Chemistry·Chao WangRenshuai Zhang
Jul 17, 2021·Cell Chemical Biology·Ashley E ModellAmit Choudhary
Jul 15, 2021·ACS Infectious Diseases·Matthew PowellKarl A Hansford
Oct 3, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Si-Wei XiaShi-Zhong Zheng
Jul 31, 2021·Journal of Biomolecular Structure & Dynamics·Muhammed ShaheerM Elizabeth Sobhia
Aug 20, 2021·European Journal of Medicinal Chemistry·Chao WangDongming Xing
Sep 25, 2020·Journal of Chemical Information and Modeling·Michael L DrummondChristopher I Williams
Aug 31, 2021·RSC Medicinal Chemistry·Chelsea E PowellNathanael S Gray
Nov 25, 2021·Molecular Microbiology·Christoph GrohmannGregor Ebert

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Datasets Mentioned

BETA
AK-104087

Methods Mentioned

BETA
ubiquitination
thermal shift
FRET
flow cytometry
neddylation
PCR

Software Mentioned

limma
R
ImageJ
Proteome Discoverer
GraphPad

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