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.

Keywords: Covid 19; RAS; Sarmesin; Sars-CoV-2; Sartans; angiotensin II; cyclic peptides; mimetics; transdermal delivery.

Figure 1

The 2D and 3D structures of well-known cyclic peptides. (a) Penicillin is one of the most powerful antibiotics. (b) Cyclosporin is a natural product used as an immunosuppressant medication. (c) Gramicidin exhibits strong antibiotic activity. (d) Insulin is a hormone that plays a key role in the regulation of blood glucose levels, and its deficiency causes diabetes.

Figure 2

Steps of the strategy to design a non-peptide ANG II mimetic. (a) ANG II peptide (the tool)—SAR studies to identify the critical amino acids. (b) Conformation (the drug door)—NMR/NOE studies to approach the bioactive conformation. (c) Cyclic peptide (prodrug) —cyclization at positions least important for activity. (d) Mimetic (the drug lead)—synthesis of a non-peptide mimetic based on critical amino acids.

Figure 3

Putative bioactive conformation of angiotensin II based on NMR spectroscopy and molecular dynamics.

Figure 4

The main components of the renin–angiotensin system are the counterbalancing axes: ACE/ANGII/AT1R (vasoconstriction), ACE2/A(1–7)/AT2R/MasR (vasorelaxation), and ACE2/alamandine/MrgD (vasorelaxation).

Figure 5

The peptide sequences of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), sarilesin [Sar¹, Ile⁸] ANGII, and sarmesin [Sar¹, Tyr (OMe)⁴] ANGII. Phenylalanine at position 8 and tyrosine at position 4 are crucial for triggering hypertensive activity.

Figure 6

Tyr, His, and Phe aromatic side chains and c-terminal carboxylate are intra connected to create a cyclic compact structure that triggers activity through Tyr hydroxylate.

Figure 7

3D structures of sarilesin and sarmesin.

Figure 8

Losartan and the active metabolite losartan carboxylic acid.

Figure 9

Correlation of pharmacophoric side chains of angiotensin II with essential groups in losartan carboxylic acid (EXP 3174).

Figure 10

Structures and activities of losartan and losartan V8 analogs.

Figure 11

Bis biphenyl alkylation of the imidazole ring of losartan V8 (analogs A,B) and losartan (analog C) by a convenient and cost-effective strategy.

Figure 12

Structures and biological activities of bis alkylated losartan (1) and losartan V8 analogs (2, 3).