Rational Design and Selection of Angiotensinogen-Targeting siRNA Candidates for the Treatment of Hypertension

Abstract

Hypertension is a major risk factor for cardiovascular disease and often requires lifelong treatment, making poor medication adherence a major clinical challenge. RNA interference offers a potential long-acting alternative by suppressing the production of disease-related proteins at the mRNA level. Angiotensinogen (AGT), the liver-derived precursor of the renin-angiotensin-aldosterone system, is a promising target because reducing AGT expression may decrease downstream angiotensin II production and lower blood pressure. In this paper, candidate small interfering RNA sequences targeting human AGT were generated and evaluated using a rational computational screening framework. All possible 21-nucleotide target windows were assessed using sequence-based criteria, including GC content, homopolymer formation, and predicted guide-strand self-pairing. Of 1,411 possible target windows, 178 passed the initial filters, and the highest-ranked candidates had GC contents between 38.1% and 47.6% with no runs of four identical nucleotides. Candidates were prioritized through composite scoring that favored moderate GC content, homopolymer avoidance, and limited predicted intramolecular structure. These results provide a focused set of AGT-targeting siRNA candidates for future evaluation of off-target effects, delivery efficiency, target accessibility, and gene-silencing activity. Because the findings are in silico, experimental validation is required before therapeutic conclusions can be drawn. This framework represents an initial computational step toward developing long-acting RNA interference therapies for hypertension.