The Crucial Role of Arginine Residues and the Arginine–Tetrazole Paradigm in Viral Infection: Therapeutic Opportunities for Tetrazole–Containing Angiotensin Receptor Blockers and Bisartans

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Arginine residues are important determinants of molecular recognition because their guanidinium groups are strongly basic and predominantly protonated at physiological pH. This enables arginine to form electrostatic interactions and multiple hydrogen bonds with anionic or polar molecular surfaces, making arginine-rich regions particularly relevant to protein–protein interactions, proteolytic processing, receptor engagement, and viral entry. The severe acute respiratory syndrome coronavirus 2019 spike glycoprotein provides a notable example, in which basic residues within the polybasic S1/S2 cleavage region (PRRARS) and the S2′ region (KPSKRS) contribute to recognition by host proteases and activation of the viral fusion machinery. Mutations or modifications to arginine residues can alter the local electrostatic environment and influence viral phenotypes. A complementary pharmacophore is the tetrazole group, which, when deprotonated, provides an anionic tetrazolate capable of engaging positively charged residues through electrostatic and hydrogen-bonding interactions. Therefore, tetrazole-containing angiotensin receptor blockers represent an intriguing chemical platform for interactions with arginine-rich viral and host proteins. This concept is extended to novel bisartans, which incorporate two anionic tetrazole-containing pharmacophores and may consequently support multivalent or cooperative electrostatic recognition. Computational, enzymatic, and biophysical investigations have proposed that sartans and bisartans can interact with several viral and host-associated targets. These include angiotensin-converting enzyme 2, S-associated regions, and furin, supporting further investigation of physicochemical recognition as a potential basis for broader antiviral activity.