Zilebesiran: Mechanism of Action

Zilebesiran: Mechanism of Action

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The safety and efficacy of zilebesiran are currently being investigated in clinical studies and have not been evaluated by the FDA or any health authority.

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 Summary

Index

RNA Interference – Mechanism of Action – Abbreviations – References

 RNA Interference

RNAi is a natural endogenous intracellular catalytic mechanism that regulates gene expression. RNAi utilizes siRNAs that are loaded onto a ribonucleoprotein complex known as the RISC to cleave and degrade specific mRNA, resulting in reduced production of the target protein.2–4

RNAi therapeutics utilize synthetic siRNA. GalNAc-conjugated siRNAs are designed to target and degrade specific mRNA in the liver following subcutaneous administration, thereby reducing the production of certain proteins.5

 Mechanism of Action

Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic that reduces the synthesis of hepatic AGT. AGT is primarily produced in the liver and is the sole precursor of all angiotensin peptides, including Ang II and aldosterone. By targeting the most upstream precursor of the RAAS, zilebesiran is designed to reduce serum AGT levels, leading to a reduction in blood pressure (Figure 1). RAAS inhibition with this approach may theoretically limit compensatory angiotensin activation associated with angiotensin‑converting-enzyme inhibition or angiotensin-receptor blockade.1

Zilebesiran consists of a synthetic siRNA covalently linked to a GalNAc ligand that binds with high affinity to the hepatic ASGPR, enabling targeted delivery to the liver.1 Following hepatocyte uptake, the siRNA associates with the RISC to enable complementary pairing with AGT mRNA, resulting in target mRNA cleavage and degradation. A single zilebesiran siRNA remains bound to the RISC for multiple cleavage cycles, acting in a catalytic manner.6–8

Figure 1. Zilebesiran Mechanism of Action.1,9

Abbreviations

ACE = angiotensin-converting enzyme; AGT = angiotensinogen; Ang I = angiotensin I; Ang II = angiotensin II; ASGPR = asialoglyoprotein receptor; GalNAc = N‑acetylgalactosamine; mRNA = messenger ribnonucleic acid; RAAS = renin‑angiotensin‑aldosterone system; RISC = RNA-induced silencing complex; RNAi = ribonucleic acid interference; siRNA = small interfering ribonucleic acid.

Updated 29 April 2026

 References

1.  Desai AS, Webb DJ, Taubel J, et al. Zilebesiran, an RNA interference therapeutic agent for hypertension. N Engl J Med. 2023;389(3):228-238. doi:10.1056/NEJMoa2208391

2.  Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411(6836):494-498. doi:10.1038/35078107

3.  Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391(6669):806-811. doi:10.1038/35888

4.  Agrawal N, Dasaradhi PVN, Mohmmed A, Malhotra P, Bhatnagar RK, Mukherjee SK. RNA Interference: Biology, mechanism, and applications. Microbiol Mol Biol Rev. 2003;67(4):657-685. doi:10.1128/MMBR.67.4.657-685.2003

5.  Jadhav V, Vaishnaw A, Fitzgerald K, Maier MA. RNA interference in the era of nucleic acid therapeutics. Nat Biotechno. 2024;42(3):394-405. doi:10.1038/s41587-023-02105-y

6.  Morosan PA, Bobu AM, Carauleanu A, et al. Zilebesiran as an innovative siRNA-based therapeutic approach for hypertension: Emerging perspectives in cardiovascular medicine. Int J Mol Sci. 2025;26(21):10717. doi:10.3390/ijms262110717

7.  An G. Pharmacokinetics and pharmacodynamics of GalNAc‐conjugated siRNAs. J Clin Pharmacol. 2023;64(1):45-57. doi:10.1002/jcph.2337

8.  Hutvágner G, Zamore PD. A microRNA in a multiple-turnover RNAi enzyme complex. Science. 2002;297(5589):2056-2060. doi:10.1126/science.1073827

9.  Touyz RM. Silencing angiotensinogen in hypertension. N Engl J Med. 2023;389(3):278-281. doi:10.1056/NEJMe2303534