Antisense Therapy for Infectious Diseases

Abstract

Infectious diseases, particularly Tuberculosis (TB) caused by Mycobacterium tuberculosis, pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most fatal disease caused by a single infectious agent. The rise of drug-resistant infectious diseases adds to the urgency of finding effective and safe intervention therapies. Antisense therapy uses antisense oligonucleotides (ASOs) that are short, chemically modified, single-stranded deoxyribonucleotide molecules complementary to their mRNA target. Due to their designed target specificity and inhibition of a disease-causing gene at the mRNA level, antisense therapy has gained interest as a potential therapeutic approach. This type of therapy is currently utilized in numerous diseases, such as cancer and genetic disorders. Currently, there are limited but steadily increasing studies available that report on the use of ASOs as treatment for infectious diseases. This review explores the sustainability of FDA-approved and preclinically tested ASOs as a treatment for infectious diseases and the adaptability of ASOs for chemical modifications resulting in reduced side effects with improved drug delivery; thus, highlighting the potential therapeutic uses of ASOs for treating infectious diseases.

Keywords: antisense oligonucleotide; antisense therapy; infectious disease; mRNA.

Figure 1

Antibacterial oligonucleotides targeting essential bacterial genes. (A1) PPNA1/2 ASOs target ftsZ mRNA and inhibit the growth of methicillin-resistant Staphylococcus aureus. (A2) PLNA787 ASO binds to ftsZ mRNA of Staphylococcus aureus to inhibit its growth. (A3) PMO ASO attaches to gyrA mRNA, causing a growth reduction in Staphylococcus aureus. (B) rpoA-PNA ASO binds to rpoA mRNA resulting in a reduction in L. monocytogenes growth. (C) polA-PNA ASO attaches to the polA mRNA, inhibiting the growth of Brucella suis. (D) The binding of acpP-PPMO ASO with the acpP mRNA results in the reduction in Acinetobacter baumannii growth. Abbreviations: ftsZ, filamentous temperature-sensitive protein Z; gyrA, gyrase A; rpoA, RNA polymerase α subunit; polA, DNA polymerase I; acpP, acyl carrier protein. Created in BioRender.com.

Figure 2

Antiviral oligonucleotides targeting essential viral genes. (A1) 3′SLT PPMO ASO targets the 3′ terminal stem-loop of the Dengue viral genome, inhibiting viral translation and RNA synthesis. (A2) Vivo-MO-1 ASO binds to the 3′ terminal stem-loop of the Dengue viral genome and inhibits the production of viral proteins. (B) Ga1Nac-LNA (SSO) ASO binds to the hepatitis B virus (HBV) transcript preventing the expression of viral antigens. (C) PMO ASO conjugated to an arginine-rich peptide (PPMO) successfully inhibited the viral replication of Ebola by attaching to the VP24 mRNA. (D) P7-PMO ASO targets the NP-v3′ site on the viral mRNA, obstructing the replication of Ebola. (E) AUG-2 PPMO ASO binds to respiratory syncytial virus (RSV)-L mRNA leading to reduced viral titers. (F) FANA ASO binds to the conserved regions of the HIV-1 genome, inhibiting HIV-1 replication. Abbreviations: 3′SLT, 3′ stem loop; Ga1NAc, N-acetylgalactosamine; NP-v3′, nucleoprotein viral genome; FANA, 2′-deoxy-2′-fluoroarabinonucleotide; HBV, Hepatitis B virus; RSV, Respiratory syncytial virus; HIV, Human immunodeficiency virus. Created in BioRender.com.

Figure 3

Antiparasitic oligonucleotides targeting essential parasitic genes. (A) GRA10-PPMO ASO downregulates GRA10 expression, resulting in growth inhibition Toxoplasma gondii. (B1) PfCRT-VMO ASO and (B2) PfDXR-PPMO ASO target the essential genes, PfCRT and PfDXR, respectively, leading to growth inhibition of Plasmodium falciparum. (B3) The binding of PNA ASO and PfSec13 results in decreased P. falciparum proliferation. (C) Antisense 5995 ASO binds to the TcIP3R mRNA of T. cruzi, inhibiting cell entry and replication. Abbreviations: GRA10, dense granule protein 10; PfCRT, P. falciparum chloroquine resistance transporter; PfDXR, P. falciparum deoxyxylulose 5-phosphate reductoisomerase; TcIP3R, T. cruzi inositol 1,4,5-trisphosphate receptor. Created in BioRender.com.

Figure 4

ASOs targeting host factors and essential bacterial genes. (A) The LNA GapmeR-ASO binds to the host lincRNA-MIR99AHG, resulting in the reduction in Mycobacterium tuberculosis in both murine and human macrophages. (B) PS-ODN ASO effectively targets the INO1 gene, resulting in reduced mycothiol levels and suppressed proliferation of M. tuberculosis. This, in turn, enhances the bacteria’s susceptibility to antibiotics (C) The 2′-OMe PGOs target the mycobacterial ald gene, leading to a significant inhibition of M. smegmatis growth within murine macrophages: LNA, locked nucleic acid; lincRNA-MIR99AHG, long intergenic noncoding RNA-MIR99AHG; PS-ODN, phosphorothioate-modified antisense oligodeoxyribonucleotide; INO1, inositol-1; M. tuberculosis, Mycobacterium tuberculosis; 2′-OMe PGOs, phosphoryl guanidine oligo-2′-O-methylribonucleotides; M. smegmatis, Mycobacterium smegmatis. Created in BioRender.com.

Figure 5

ASOs targeting host factors during various viral infections in the host cell. (A) ACE2 ASO binds to the ACE2 receptor, inhibiting the entry of SARS-CoV-2. (B) PNA ASO attaches to miR-122, preventing HCV viral genome stabilization and replication. (C) LNA-PS ASO inhibits Ebola membrane fusion and prevents ribonucleoprotein (RNP) release by binding to NPC1 mRNA. (D) PROP5 ASO binds to PDCD5 mRNA, resulting in the inhibition of programmed cell death and H1N1 influenza viral replication. (E) ASODN2 ASO hinders HBV replication by binding to the ASGPR1 receptor. (F) The binding of VIVO-PMO ASO to MRJ-L isoform results in the inhibition of HIV-1’s nuclear entry and genome integration, as well as the RSV’s viral RNA and mRNA expression. Abbreviations: ACE2, angiotensin-converting enzyme 2; miR-122, microRNA-122; NPC1, Niemann–Pick C1; PDCD5, programmed cell death protein 5; ASGPR1, asialoglycoprotein receptor 1; MRJ-L, Mammalian relative of DnaJ; HCV, Hepatitis C virus. Created in BioRender.com.