Peptidic defective interfering gene nanoparticles against Omicron, Delta SARS-CoV-2 variants and influenza A virus in vivo

Abstract

Defective interfering genes (DIGs) are short viral genomes and interfere with wild-type viral replication. Here, we demonstrate that the new designed SARS-CoV-2 DIG (CD3600) can significantly inhibit the replication of SARS-CoV-2 including Alpha, Delta, Kappa and Omicron variants in human HK-2 cells and influenza DIG (PAD4) can significantly inhibit influenza virus replication in human A549 cells. One dose of influenza DIGs prophylactically protects 90% mice from lethal challenge of A(H1N1)pdm09 virus and CD3600 inhibits SARS-CoV-2 replication in hamster lungs when DIGs are administrated to lungs one day before viral challenge. To further investigate the gene delivery vector in the respiratory tract, a peptidic TAT2-P1&LAH4, which can package genes to form small spherical nanoparticles with high endosomal escape ability, is demonstrated to dramatically increase gene expression in the lung airway. TAT2-P1&LAH4, with the dual-functional TAT2-P1 (gene-delivery and antiviral), can deliver CD3600 to significantly inhibit the replication of Delta and Omicron SARS-CoV-2 in hamster lungs. This peptide-based nanoparticle system can effectively transfect genes in lungs and deliver DIGs to inhibit SARS-CoV-2 variants and influenza virus in vivo, which provides the new insight into the drug delivery system for gene therapy against respiratory viruses.

Generation of “OP7 chimera” defective interfering particle preparations free of infectious influenza A virus that shows antiviral efficacy in mice

“…5E). A similarly high antiviral activity was found for DIPs derived from IAV and from other viral species in different animal models [5,16,[18][19][20][21][22][23][24][25]40]. Together, these results demonstrate the safety and antiviral activity of DIPs and the potential for their in vivo use as antivirals.…”

“…6). These results (and those of other groups [5,16,[20][21][22][23][24][25]40]) clearly suggest that common concerns regarding adverse effects (e.g., cytokine storm, lung damage) due to DIP administration in animals can be abandoned and that DIPs, as defective, non-replicating viral particles might also be suitable for safe clinical applications in humans. Moreover, coinfection with a lethal dose of STV together with OP7 chimera DIPs resulted in 100% survival of the mice (Fig.…”

“…In particular, IAV-derived DIPs resulted in a high tolerability and antiviral efficacy in animal studies [5,16,[18][19][20][21][22][23][24][25], and were therefore proposed as prophylactic and therapeutic antivirals [16,[25][26][27]. IAV DIPs typically contain a large internal deletion in one of the eight genomic viral RNA (vRNA) segments [4,10,16,22,25,26,[28][29][30].…”

Generation of “OP7 chimera” defective interfering influenza A particle preparations free of infectious virus that show antiviral efficacy in mice

“…6 A). These results (and those of other groups 5 , 16 , 20 – 25 , 40 ) clearly suggest that common concerns regarding adverse effects (e.g., cytokine storm, lung damage) due to DIP administration in animals can be abandoned and that DIPs, as defective, non-replicating viral particles might also be suitable for safe clinical applications in humans. Moreover, co-infection with a lethal dose of STV together with OP7 chimera DIPs resulted in 100% survival of the mice (Fig.…”

Defective Interfering Particles of Influenza Virus and Their Characteristics, Impacts, and Use in Vaccines and Antiviral Strategies: A Systematic Review

“…TAT-P1/DIG-3 showed significant antiviral activity against A/HongKong/415742Md/2009 (H1N1) and A/Netherlands/219/2003 (H7N7) infection in mice, exhibiting superiority compared with treatment of zanamivir [99]. Furthermore, the same research group developed DIG-4, wherein the segment 3 DVG in DIG-3 was replaced with a shorter one and packaged by an improved delivery peptide TAT2-P1; it showed stronger antiviral activity in mice [100].…”