Novel benzimidazole angiotensin receptor blockers with anti-SARS-CoV-2 activity equipotent to that of nirmatrelvir: computational and enzymatic studies

ABSTRACT

Background

Hypertension worsens outcomes in SARS-CoV-2 patients. Sartans, a type of antihypertensive angiotensin receptor blocker-(ARB), reduce COVID-19 morbidity and mortality by targeting angiotensin-converting enzyme-2 (ACE2). This study aimed to evaluate the antiviral and antihypertensive effects of nirmatrelvir, commercial sartans (candesartan, losartan, and losartan carboxylic (Exp3174)), and newly synthesized sartans (benzimidazole-N-biphenyl carboxyl (ACC519C) and benzimidazole-N-biphenyl tetrazole (ACC519T)), compared to nirmatrelvir, the antiviral component of Paxlovid.

Research design and methods

Surface plasmon resonance (SPR) and enzymatic studies assessed drug effects on ACE2. Antiviral abilities were tested with SARS-CoV-2-infected Vero E6 cells, and antihypertensive effects were evaluated using angiotensin II-contracted rabbit iliac arteries.

Results

Benzimidazole-based candesartan and ACC519C showed antiviral activity comparable to nirmatrelvir (95% inhibition). Imidazole-based losartan, Exp3174, and ACC519T were less potent (75%–80% and 50%, respectively), with Exp3174 being the least effective. SPR analysis indicated high sartans-ACE2 binding affinity. Candesartan and nirmatrelvir combined had greater inhibitory and cytopathic effects (3.96%) than individually (6.10% and 5.08%). ACE2 enzymatic assays showed varying effects of novel sartans on ACE2. ACC519T significantly reduced angiotensin II-mediated contraction, unlike nirmatrelvir and ACC519T(2).

Conclusion

This study reports the discovery of a new class of benzimidazole-based sartans that significantly inhibit SARS-CoV-2, likely due to their interaction with ACE2.

KEYWORDS:

• Angiotensin receptor blockers
• bisartans
• coronavirus 2019
• sartans
• severe acute respiratory syndrome coronavirus 2

Declaration of interest

A Zulli co-owns Zultek Engineering, the provider of product OB16 bath systems. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Conceptualization and coordination, CT Chasapis and JM Matsoukas; molecular dynamic calculations, H Ridgway, T Mavromoustakos, I Karakasiliotis., and CT Chasapis; experimental work and methodology, LK Gadanec, A Zulli, V Apostolopoulos., K. Węgrzyn, N Vassilaki, G Mpekoulis, P Giastas., M Zouridakis, K. Kelaidonis., VG Gorgoulis. I Karakasiliotis., CT Chasapis; writing – original draft preparation, GJ Moore, N Vassilaki, CT Chasapis and JM Matsoukas.; writing – review and editing, A Zulli, V Apostolopoulos, N Vassilaki, S Tsiodras, VG Gorgoulis, CT Chasapis and JM Matsoukas. All authors have read and agreed to the published version of the manuscript.

Acknowledgments

This publication is part of the ELPanvir Consortium. GJ Moore would like to thank PepMetics for its support. JM Matsoukas would like to thank the General Secretariat for Research and Technology, the Patras Science Park, the Region of Western Greece (Research and Technology), and the pharmaceutical companies Eli Lilly Greece and Uni-Pharma for supporting his research in multiple sclerosis, hypertension, and COVID-19. A Zulli, V Apostolopoulos., and LK Gadanec. would like to thank the support from the Institute for Health and Sport, Victoria University, Werribee campus, Melbourne, Australia. LK Gadanec was supported by a Victoria University postgraduate scholarship. LK Gadanec., V Apostolopoulos. A Zulli. would also like to acknowledge the outstanding support from Steven Holloway with animal care (Victoria University Animal Services, Werribee Campus). I Karakasiliotis and VG Gorgoulis are thankful to Bodosakis Foundation for funding the work in Biosafety level 3 facility. CT Chasapis would like to thank the National Research Foundation (NHRF) for supporting the research work by providing a Research Seed Grant. We thank Mr Nikolaos Maniotis for typing, editing, and proofreading this manuscript.

Data availability statement

The data underlying this study are not publicly available due to commercial and IP value. The data are available from the corresponding author upon reasonable request.

Supplementary materials

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14728222.2024.2362675

Additional information

Funding

V Apostolopoulos and H Ridgway were supported by a Planetary Health Grant PH098 from Victoria University. V Apostolopoulos would like to thank the Greek Orthodox Archdiocese of Australia funds, and the VU COVID-19 Appeal Funds, whose generous support made possible the research of this paper. VG Gorgoulis received support from the National Public Investment Program of the Ministry of Development and Investment/General Secretariat for Research and Technology, in the framework of the Flagship Initiative to address SARS-CoV-2 (2020ΣΕ01300001); the Welfare Foundation for Social & Cultural Sciences, Athens, Greece; H. Pappas donation; the Hellenic Foundation for Research and Innovation grants no. 775 (Hippo) and 3782 (PACOREL). T Mavromoustakos and I Karakasiliotis were supported by National Kapodistrian University of Athens Special Account for Research Grants (70/3/8916). The work of N Vassilaki and G Mpekoulis was supported by the International Pasteur Network Grant ACIP505-2022/CoV-Catechol, coordinated by N Vassilaki. G Mpekoulis was supported by an excellence PhD scholarship from Hellenic Pasteur Institute in the context of NOSTOS donation. The work of N Vassilaki was supported by the International Pasteur Network grant ACIP 505-22.