Discovery of Novel GPVI Receptor Antagonists by Structure-based Repurposing

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Jun 28

PMID 24971515

Citations 12

Authors

Lewis Taylor

Sridhar R Vasudevan

Chris I Jones

Jonathan M Gibbins

Grant C Churchill

R Duncan Campbell

Carmen H Coxon

Affiliations

Soon will be listed here.

Abstract

Inappropriate platelet aggregation creates a cardiovascular risk that is largely managed with thienopyridines and aspirin. Although effective, these drugs carry risks of increased bleeding and drug 'resistance', underpinning a drive for new antiplatelet agents. To discover such drugs, one strategy is to identify a suitable druggable target and then find small molecules that modulate it. A good and unexploited target is the platelet collagen receptor, GPVI, which promotes thrombus formation. To identify inhibitors of GPVI that are safe and bioavailable, we docked a FDA-approved drug library into the GPVI collagen-binding site in silico. We now report that losartan and cinanserin inhibit GPVI-mediated platelet activation in a selective, competitive and dose-dependent manner. This mechanism of action likely underpins the cardioprotective effects of losartan that could not be ascribed to its antihypertensive effects. We have, therefore, identified small molecule inhibitors of GPVI-mediated platelet activation, and also demonstrated the utility of structure-based repurposing.

Citing Articles

The humanized platelet glycoprotein VI Fab inhibitor EMA601 protects from arterial thrombosis and ischaemic stroke in mice.

Navarro S, Talucci I, Gob V, Hartmann S, Beck S, Orth V Eur Heart J. 2024; 45(43):4582-4597.

PMID: 39150906 PMC: 11560278. DOI: 10.1093/eurheartj/ehae482.

Ultra-high throughput-based screening for the discovery of antiplatelet drugs affecting receptor dependent calcium signaling dynamics.

Fernandez D, Troitino S, Sobota V, Tullemans B, Zou J, van den Hurk H Sci Rep. 2024; 14(1):6229.

PMID: 38486006 PMC: 10940705. DOI: 10.1038/s41598-024-56799-4.

A Comparative Assessment Study of Known Small-molecule GPVI Modulators.

Foster H, Wilson C, Gauer J, Xu R, Howard M, Manfield I ACS Med Chem Lett. 2022; 13(2):171-181.

PMID: 35178172 PMC: 8842102. DOI: 10.1021/acsmedchemlett.1c00414.

Candida albicans elicits protective allergic responses via platelet mediated T helper 2 and T helper 17 cell polarization.

Wu Y, Zeng Z, Guo Y, Song L, Weatherhead J, Huang X Immunity. 2021; 54(11):2595-2610.e7.

PMID: 34506733 PMC: 8585696. DOI: 10.1016/j.immuni.2021.08.009.

Monosubstituted Coumarins Inhibit Epinephrine-induced Platelet Aggregation.

Jimenez-Orozco F, Galicia-Zapatero S, Lopez-Lopez E, Medina-Franco J, Cedeno F, Flores-Garcia M Cardiovasc Hematol Agents Med Chem. 2021; 20(1):43-51.

PMID: 33906594 PMC: 9127734. DOI: 10.2174/1871525719666210427132808.

References

ODonnell C, Larson M, Feng D, Sutherland P, Lindpaintner K, Myers R . Genetic and environmental contributions to platelet aggregation: the Framingham heart study. Circulation. 2001; 103(25):3051-6. DOI: 10.1161/01.cir.103.25.3051. View

Roger V, Go A, Lloyd-Jones D, Benjamin E, Berry J, Borden W . Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation. 2011; 125(1):e2-e220. PMC: 4440543. DOI: 10.1161/CIR.0b013e31823ac046. View

Ungerer M, Rosport K, Bultmann A, Piechatzek R, Uhland K, Schlieper P . Novel antiplatelet drug revacept (Dimeric Glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans. Circulation. 2011; 123(17):1891-9. DOI: 10.1161/CIRCULATIONAHA.110.980623. View

Lindholm L, Ibsen H, Dahlof B, Devereux R, Beevers G, de Faire U . Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359(9311):1004-10. DOI: 10.1016/S0140-6736(02)08090-X. View

Yeung J, Holinstat M . Newer agents in antiplatelet therapy: a review. J Blood Med. 2012; 3:33-42. PMC: 3393068. DOI: 10.2147/JBM.S25421. View

Bal Dit Sollier C, Crassard I, Simoneau G, Bergmann J, Bousser M, Drouet L . Effect of the thromboxane prostaglandin receptor antagonist terutroban on arterial thrombogenesis after repeated administration in patients treated for the prevention of ischemic stroke. Cerebrovasc Dis. 2009; 28(5):505-13. DOI: 10.1159/000236915. View

Ono K, Ueda H, Yoshizawa Y, Akazawa D, Tanimura R, Shimada I . Structural basis for platelet antiaggregation by angiotensin II type 1 receptor antagonist losartan (DuP-753) via glycoprotein VI. J Med Chem. 2010; 53(5):2087-93. DOI: 10.1021/jm901534d. View

Smethurst P, Joutsi-Korhonen L, OConnor M, Wilson E, Jennings N, Garner S . Identification of the primary collagen-binding surface on human glycoprotein VI by site-directed mutagenesis and by a blocking phage antibody. Blood. 2003; 103(3):903-11. DOI: 10.1182/blood-2003-01-0308. View

Mizushima T . Drug discovery and development focusing on existing medicines: drug re-profiling strategy. J Biochem. 2011; 149(5):499-505. DOI: 10.1093/jb/mvr032. View

10.

Maree A, Curtin R, Chubb A, Dolan C, Cox D, OBrien J . Cyclooxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost. 2005; 3(10):2340-5. DOI: 10.1111/j.1538-7836.2005.01555.x. View

11.

Muzard J, Bouabdelli M, Zahid M, Ollivier V, Lacapere J, Jandrot-Perrus M . Design and humanization of a murine scFv that blocks human platelet glycoprotein VI in vitro. FEBS J. 2009; 276(15):4207-22. DOI: 10.1111/j.1742-4658.2009.07129.x. View

12.

Kehoe P, Passmore P . The renin-angiotensin system and antihypertensive drugs in Alzheimer's disease: current standing of the angiotensin hypothesis?. J Alzheimers Dis. 2012; 30 Suppl 2:S251-68. DOI: 10.3233/JAD-2012-111376. View

13.

Chen L, Gui C, Luo X, Yang Q, Gunther S, Scandella E . Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro. J Virol. 2005; 79(11):7095-103. PMC: 1112131. DOI: 10.1128/JVI.79.11.7095-7103.2005. View

14.

Ashburn T, Thor K . Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004; 3(8):673-83. DOI: 10.1038/nrd1468. View

15.

Yang Q, Chen L, He X, Gao Z, Shen X, Bai D . Design and synthesis of cinanserin analogs as severe acute respiratory syndrome coronavirus 3CL protease inhibitors. Chem Pharm Bull (Tokyo). 2008; 56(10):1400-5. DOI: 10.1248/cpb.56.1400. View

16.

Ballester P, Mangold M, Howard N, Marchese Robinson R, Abell C, Blumberger J . Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification. J R Soc Interface. 2012; 9(77):3196-207. PMC: 3481598. DOI: 10.1098/rsif.2012.0569. View

17.

Goebel S, Li Z, Vogelmann J, Holthoff H, Degen H, Hermann D . The GPVI-Fc fusion protein Revacept improves cerebral infarct volume and functional outcome in stroke. PLoS One. 2013; 8(7):e66960. PMC: 3720811. DOI: 10.1371/journal.pone.0066960. View

18.

Konstam M, Neaton J, Dickstein K, Drexler H, Komajda M, Martinez F . Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009; 374(9704):1840-8. DOI: 10.1016/S0140-6736(09)61913-9. View

19.

Bostrom J, Greenwood J, Gottfries J . Assessing the performance of OMEGA with respect to retrieving bioactive conformations. J Mol Graph Model. 2003; 21(5):449-62. DOI: 10.1016/s1093-3263(02)00204-8. View

20.

Michelson A . Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov. 2010; 9(2):154-69. DOI: 10.1038/nrd2957. View