Advanced morpholino oligomers: A novel approach to antiviral therapy

Abstract

Phosphorodiamidate morpholino oligomers (PMOs) are synthetic antisense oligonucleotide analogs that are designed to interfere with translational processes by forming base-pair duplexes with specific RNA sequences. Positively charged PMOs (PMOplus™) are effective for the postexposure protection of two fulminant viral diseases, Ebola and Marburg hemorrhagic fever in nonhuman primates, and this class of antisense agent may also have possibilities for treatment of other viral diseases. PMOs are highly stable, are effective by a variety of routes of administration, can be readily formulated in common isotonic delivery vehicles, and can be rapidly designed and synthesized. These are properties which may make PMOs good candidates for use during responses to emerging or reemerging viruses that may be insensitive to available therapies or for use during outbreaks, especially in regions that lack a modern medical infrastructure. While the efficacy of sequence-specific therapies can be limited by target-site sequence variations that occur between variants or by the emergence of resistant mutants during infections, various PMO design strategies can minimize these impacts. These strategies include the use of promiscuous bases such as inosine to compensate for predicted base-pair mismatches, the use of sequences that target conserved sites between viral strains, and the use of sequences that target host products that viruses utilize for infection.

AVI-7288 for Marburg Virus in Nonhuman Primates and Humans

“…[12][13][14] AVI-7288, a drug intended for the postexposure prophylaxis of MARV infection, is a 23-mer antisense phosphorodiamidate morpholino oligomer (PMO) with positively charged residues incorporated in its backbone. 15 AVI-7288 specifically targets the messenger RNA (mRNA) sequence of the MARV nucleoprotein, the major nucleoprotein involved in RNA encapsidation, physically blocking its translation 16 (Fig. 1).…”

Antisense Oligonucleotids and Antibacterial Use

“…• Ribozomun okuma yapması için diziyi tanı-yacağı bölge olan 5' cap oluşumunun engellenmesi şeklinde açıklanabilir (4,6) .…”

Therapeutics for Postexposure Treatment of Ebola Virus Infection

“…Antisense-PMOs are nuclease-resistant and water-soluble single-stranded DNA analogs that can enter cells and form stable duplex with complementary RNA [49]. PMOs are easy to synthesize and they can be administered in the isotonic delivery vehicles [53]. Recently, a combination of two PMOs (AVI-6002) consisting of AVI-7537 targeting the VP24 gene and AVI-7539 targeting VP35 has been developed and optimized by Sarepta Therapeutics under contract with US Department of Defense.…”

“…Because PMOs are sequence-specific DNAs, the efficacy of therapeutics depends on the existence of the conserved targeting sequences and can be offset by the emergence of the resistant mutants. This problem can be overcome by the use of several targeting sequences against conserved viral sites or the site important for the interaction with host proteins, and also by mutated PMOs that may compensate for the predicted base-pair mismatches [53]. …”