From Angiotensin II to Cyclic Peptides and Angiotensin Receptor Blockers (ARBs): Perspectives of ARBs in COVID-19 Therapy

Abstract

The octapeptide hormone angiotensin II is one of the most studied peptides with the aim of designing and synthesizing non-peptide mimetics for oral administration. To achieve this, cyclizations at different positions within the peptide molecule has been a useful strategy to define the active conformation. These studies on angiotensin II led to the discovery of Sarmesin, a type II angiotensin II antagonist, and the breakthrough non-peptide mimetic Losartan, the first in a series of sartans marketed as a new generation of anti-hypertensive drugs in the 1990s. Angiotensin II receptor blockers (ARBS) and angiotensin I converting enzyme inhibitors (ACEI) were recently reported to protect hypertensive patients infected with SARS-CoV-2. The renin–angiotensin system (RAS) inhibitors reduce excess angiotensin II and increase antagonist heptapeptides alamandine and aspamandine which counterbalance angiotensin II and maintain homeostasis and vasodilation.

Receptor Interactions of Angiotensin II and Angiotensin Receptor Blockers—Relevance to COVID-19

“…The Phe8 ring of Ang II, which is essential for agonist activity, may have a functional role in guiding the Y35 ring through quadrupolar ring:ring interactions into the correct alignment for receptor activation. Such considerations have led to the development of a new generation of nonpeptide Ang II mimetics as potential drugs for treating hypertension and other cardiovascular diseases, including bisartans [12,13,19]. Recent clinical findings from hospitalized hypertensive patients infected by SARS-CoV-2 have shown a protective effect against the infection by the virus and reduction of morbidity and mortality.…”

“…However, further studies are required to determine if the vasoconstriction shown at the higher doses of Ang II could be reduced or blocked by increasing/decreasing the dose of BV6(TFA). zyme 2 (ACE2) and the renin-angiotensin system (RAS) inhibitors reduce excess AngII and increase the antagonist heptapeptides alamandine and aspamandine, which counterbalance Ang II and maintain homeostasis and vasodilation [13]. In particular, the CRS of Ang II described in the study well-explains tyrosine-based ligand-receptor interactions and can be applied to the new aggressive SARS-CoV-2 mutations, which is a pressing issue.…”

“…This model of receptor interaction (Figure 5) has enabled the development of more potent nonpeptide Ang II mimetics as potential drugs for treating hypertension and other cardiovascular diseases [12,13]. These new generations of drugs, called bisartans, contain two tetrazole groups (the carboxylate present in all insurmountable ARBs was replaced by its functional mimetic tetrazole) that are mounted on an imidazole template as biphenyl tetrazole groups.…”

“…The RAS and in particular ACE2 are the entry points of the virus, and this study significantly contributes to the understanding of the molecular mechanisms of Ang II and, subsequently, the driving forces that lead to the infectivity and transmissibility of the new mutations. We already reported the first evidence for the benefit of ARBs as promising repurposed drugs to treat infection in recent publications [13,[15][16][17][18][19].…”

COVID-19 Vaccines in the Pipeline, Are Antibodies Adequate?

“…SARS-CoV-2 typically enters the body through the nose and throat. It then binds to and invades the cells of the upper respiratory tract which are rich in angiotensin-converting enzyme 2 (ACE2) receptor [6]; although recently it has been shown that SARS-CoV-2 can also enter host cells via several different receptors [7][8][9]. If the individual's immune system is able to repel the virus during this initial phase (via the generation of neutralization antibodies), it is able to move down to infect the lung parenchyma, where it becomes significantly more dangerous.…”