More-powerful Virus Inhibitors from Structure-based Analysis of HEV71 Capsid-binding Molecules

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2014 Feb 11

PMID 24509833

Citations 48

Authors

Luigi De Colibus

Xiangxi Wang

John A B Spyrou

James Kelly

Jingshan Ren

Jonathan Grimes

Gerhard Puerstinger

Nicola Stonehouse

Thomas S Walter

Zhongyu Hu

Junzhi Wang

Xuemei Li

Wei Peng

David Rowlands

Elizabeth E Fry

Zihe Rao

David I Stuart

Affiliations

Soon will be listed here.

Abstract

Enterovirus 71 (HEV71) epidemics in children and infants result mainly in mild symptoms; however, especially in the Asia-Pacific region, infection can be fatal. At present, no therapies are available. We have used structural analysis of the complete virus to guide the design of HEV71 inhibitors. Analysis of complexes with four 3-(4-pyridyl)-2-imidazolidinone derivatives with varying anti-HEV71 activities pinpointed key structure-activity correlates. We then identified additional potentially beneficial substitutions, developed methods to reliably triage compounds by quantum mechanics-enhanced ligand docking and synthesized two candidates. Structural analysis and in vitro assays confirmed the predicted binding modes and their ability to block viral infection. One ligand (with IC50 of 25 pM) is an order of magnitude more potent than the best previously reported inhibitor and is also more soluble. Our approach may be useful in the design of effective drugs for enterovirus infections.

Citing Articles

Tanomastat exerts multi-targeted inhibitory effects on viral capsid dissociation and RNA replication in human enteroviruses.

Lim T, Jaladanki C, Wong Y, Yogarajah T, Fan H, Chu J EBioMedicine. 2024; 107:105277.

PMID: 39226680 PMC: 11419895. DOI: 10.1016/j.ebiom.2024.105277.

Chemoproteomics enables identification of coatomer subunit zeta-1 targeted by a small molecule for enterovirus A71 inhibition.

Li X, Zhang J, Xiao Y, Song H, Li Y, Li W MedComm (2020). 2024; 5(6):e587.

PMID: 38840773 PMC: 11151152. DOI: 10.1002/mco2.587.

Insights into enterovirus a-71 antiviral development: from natural sources to synthetic nanoparticles.

Feferbaum-Leite S, Santos I, Grosche V, da Silva G, Jardim A Arch Microbiol. 2023; 205(10):334.

PMID: 37730918 DOI: 10.1007/s00203-023-03660-3.

Advances in anti-EV-A71 drug development research.

Wang S, Pang Z, Fan H, Tong Y J Adv Res. 2023; 56:137-156.

PMID: 37001813 PMC: 10834817. DOI: 10.1016/j.jare.2023.03.007.

Hand, Foot, and Mouth Disease Challenges and Its Antiviral Therapeutics.

Li Z, Ji W, Chen S, Duan G, Jin Y Vaccines (Basel). 2023; 11(3).

PMID: 36992155 PMC: 10054684. DOI: 10.3390/vaccines11030571.

References

Winn M, Ballard C, Cowtan K, Dodson E, Emsley P, Evans P . Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 4):235-42. PMC: 3069738. DOI: 10.1107/S0907444910045749. View

Plevka P, Perera R, Yap M, Cardosa J, Kuhn R, Rossmann M . Structure of human enterovirus 71 in complex with a capsid-binding inhibitor. Proc Natl Acad Sci U S A. 2013; 110(14):5463-7. PMC: 3619292. DOI: 10.1073/pnas.1222379110. View

Ke Y, Lin T . Modeling the ligand-receptor interaction for a series of inhibitors of the capsid protein of enterovirus 71 using several three-dimensional quantitative structure-activity relationship techniques. J Med Chem. 2006; 49(15):4517-25. DOI: 10.1021/jm0511886. View

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

Tsang S, Cheh J, Isaacs L, Joseph-McCarthy D, Choi S, Pevear D . A structurally biased combinatorial approach for discovering new anti-picornaviral compounds. Chem Biol. 2001; 8(1):33-45. DOI: 10.1016/s1074-5521(00)00053-3. View

Hadfield A, Oliveira M, Kim K, Minor I, Kremer M, Heinz B . Structural studies on human rhinovirus 14 drug-resistant compensation mutants. J Mol Biol. 1995; 253(1):61-73. DOI: 10.1006/jmbi.1995.0536. View

Feil S, Hamilton S, Krippner G, Lin B, Luttick A, McConnell D . An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus. ACS Med Chem Lett. 2014; 3(4):303-7. PMC: 4025830. DOI: 10.1021/ml2002955. View

Axford D, Owen R, Aishima J, Foadi J, Morgan A, Robinson J . In situ macromolecular crystallography using microbeams. Acta Crystallogr D Biol Crystallogr. 2012; 68(Pt 5):592-600. PMC: 4791750. DOI: 10.1107/S0907444912006749. View

Banks J, Beard H, Cao Y, Cho A, Damm W, Farid R . Integrated Modeling Program, Applied Chemical Theory (IMPACT). J Comput Chem. 2005; 26(16):1752-80. PMC: 2742605. DOI: 10.1002/jcc.20292. View

10.

Cho A, Guallar V, Berne B, Friesner R . Importance of accurate charges in molecular docking: quantum mechanical/molecular mechanical (QM/MM) approach. J Comput Chem. 2005; 26(9):915-31. PMC: 3920598. DOI: 10.1002/jcc.20222. View

11.

Joseph-McCarthy D, Tsang S, Filman D, Hogle J, Karplus M . Use of MCSS to design small targeted libraries: application to picornavirus ligands. J Am Chem Soc. 2001; 123(51):12758-69. DOI: 10.1021/ja003972f. View

12.

PHELPS D, Post C . A novel basis of capsid stabilization by antiviral compounds. J Mol Biol. 1995; 254(4):544-51. DOI: 10.1006/jmbi.1995.0637. View

13.

Tetko I, Gasteiger J, Todeschini R, Mauri A, Livingstone D, Ertl P . Virtual computational chemistry laboratory--design and description. J Comput Aided Mol Des. 2005; 19(6):453-63. DOI: 10.1007/s10822-005-8694-y. View

14.

Joseph-McCarthy D, Hogle J, Karplus M . Use of the multiple copy simultaneous search (MCSS) method to design a new class of picornavirus capsid binding drugs. Proteins. 1997; 29(1):32-58. DOI: 10.1002/(sici)1097-0134(199709)29:1<32::aid-prot3>3.0.co;2-h. View

15.

Nicholls R, Long F, Murshudov G . Low-resolution refinement tools in REFMAC5. Acta Crystallogr D Biol Crystallogr. 2012; 68(Pt 4):404-17. PMC: 3322599. DOI: 10.1107/S090744491105606X. View

16.

Plevka P, Perera R, Cardosa J, Kuhn R, Rossmann M . Crystal structure of human enterovirus 71. Science. 2012; 336(6086):1274. PMC: 3448362. DOI: 10.1126/science.1218713. View

17.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

18.

Shia K, Li W, Chang C, Hsu M, Chern J, Leong M . Design, synthesis, and structure-activity relationship of pyridyl imidazolidinones: a novel class of potent and selective human enterovirus 71 inhibitors. J Med Chem. 2002; 45(8):1644-55. DOI: 10.1021/jm010536a. View

19.

Chen V, Arendall 3rd W, Headd J, Keedy D, Immormino R, Kapral G . MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):12-21. PMC: 2803126. DOI: 10.1107/S0907444909042073. View

20.

Rotbart H . Treatment of picornavirus infections. Antiviral Res. 2001; 53(2):83-98. DOI: 10.1016/s0166-3542(01)00206-6. View