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

BACKGROUND: Pre-existing hypertensive pathologies are linked to worsened outcomes in patients infected with severe-acute respiratory syndrome (SARS-CoV-2). Sartans, a family of anti-hypertensive angiotensin receptor blockers (ARBs), reduce morbidity and mortality in coronavirus 2019 patients by aeffecting angiotensin-converting enzyme-2 (ACE2). The purpose of this study was to determine the anti-SARS-CoV-2viral and antihypertensive abilities of nirmatrelvir, and commercially available (e.g. candesartan, losartan, and losartan carboxylic (Exp3174))) and newly synthesized sartans (e.g. 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-binding (SPR) and enzymatic studies were used to determine drug effect on ACE2, antiviral abilities were evaluated using Vero E6 cells infected with SARS-CoV-2 and antihypertensive effects were investigated using rabbit iliac arteries contracted to angiotensin II-dose response.

RESULTS: The antiviral activity of benzimidazole-based candesartan and ACC519C were equipotent with nirmatrelvir (95% inhibition), while the imidazole-based losartan and E×p3174and ACC519T were less potent (75-80 and 50%, respectively%) and E×p3174was the least effective (50%). Furthermore, SPR analysis revealed a high binding affinity of sartans for ACE2 protein. Moreover, candesartan and nirmatrelvir exhibited the greatest inhibitory and cytopathic effect (3.96%) when given in combination rather than individually (6.10% and 5.08%, respectively). In addition,The ACE2 enzymatic activity assays demonstrated enhancement or inhibition properties of novel sartans toward ACE2 enzyme. Lastly, ACC519T potently reduced angiotensin II-mediated contraction while nirmatrelvir and ACC519T(2) had no effect.

CONCLUSION: This study describes the discovery of a new class of benzimidazole-based sartans that drastically inhibit SARS-CoV-2, which could be attributed, at least in part, to their interaction with ACE2.