GalNAc-siRNA conjugates: Prospective tools on the frontier of anti-viral therapeutics

Abstract

The growing use of short-interfering RNA (siRNA)-based therapeutics for viral diseases reflects the most recent innovations in anti-viral vaccines and drugs. These drugs play crucial roles in the fight against many hitherto incurable diseases, the causes, pathophysiologies, and molecular processes of which remain unknown. Targeted liver drug delivery systems are in clinical trials. The receptor-mediated endocytosis approach involving the abundant asialoglycoprotein receptors (ASGPRs) on the surfaces of liver cells show great promise. We here review N -acetylgalactosamine (GalNAc)-siRNA conjugates that treat viral diseases such as hepatitis B infection, but we also mention that novel, native conjugate-based, targeted siRNA anti-viral drugs may also cure several life-threatening diseases such as hemorrhagic cystitis, multifocal leukoencephalopathy, and severe acute respiratory syndrome caused by coronaviruses and human herpes virus.

RNA Therapeutic Options to Manage Aberrant Signaling Pathways in Hepatocellular Carcinoma: Dream or Reality?

“…Manufactured siRNA-based therapeutics use siRNAs that have been chemically stabilized to increase their potency and reduce RNase degradation in vivo but challenges remain due to off-target effects, as well as unintended immunogenic reaction ( 7 ). The stabilization and delivery of siRNA is, therefore, a critical issue ( 8 ).…”

“…Upon cell entry the NPs can be separated (cleaved) to facilitate RNA loading into an AGO based RISC. For example, a Ga1NAc-siRNA conjugate readily binds to ASGPR thus providing siRNA entry access to hepatocytes ( 8 , 33 ). Antibodies are also efficient delivery vehicles for cell specific delivery because they are stable in vivo and also specific to a chosen target ( 34 ).…”

Noncoding RNAs Emerging as Drugs or Drug Targets: Their Chemical Modification, Bio-Conjugation and Intracellular Regulation

“…It is able to bind specifically to the trimeric desialic acid glycoprotein receptor (ASGPR) (Kd = 2.5 nM), which is highly expressed on the surface of liver cells. The strategy of modifying GalNAc on siRNA for targeted delivery has been widely used [ 76 , 77 , 78 ]. Revusiran, the first GalNAc-siRNA coupling that enters clinical trials, primarily targets the thyrotropin transport protein mRNA to inhibit gene expression for the treatment of hereditary transthyretin amyloidosis (hATTR).…”

The therapeutic prospects of N-acetylgalactosamine-siRNA conjugates

“…As previously mentioned, GalNAc-siRNA conjugates are commonly used in liver diseases ( Springer and Dowdy, 2018 ; Willoughby et al, 2018 ; Thangamani et al, 2021 ). The development of GalNAc-siRNA conjugates can help to boost oligonucleotide drug popularity by removing barriers such as poor drug safety, efficacy, and specificity posed by other delivery systems.…”