Biochemical Prevention and Treatment via targeting on viral mRNA
Targeting viral mRNA is one of the most active areas of research and development. Several strategies have emerged over the years and are being tested pre-clinically and clinically. They include: antisense-oligonucleotides (AS-ONs), ribozymes, and recently, RNA interference (RNAi). All these strategies share the features of conceptual simplicity, straightforward drug design and quick route to identify drug leads. However, the challenges have been to improve potency, pharmacokinetics and, most importantly, intracellular delivery of the drug candidates. As the oldest strategy, AS-ON technology has produced to date one drug in the market place, Vitravene®. A number of clinical trials of drug candidates from these technologies are currently ongoing.
Antisense-oligonucleotides
Antisense-oligonucleotides (AS-ONs) are short synthetic oligonucleotides that form complementary pair with specific viral mRNA targets. AS-ONs inhibit viral protein production by both blocking viral mRNA translation and triggering its degradation. Since the discovery of viral inhibition effect of AS-ONs by Zamecnik and Stephenson in 1978 [28], antisense technology has been developed as a powerful tool for target validation and therapeutic purposes.
Vitravene is the first AS-ON based drug approved by FDA. Vitravene, or fomivirsen sodium, is a 21-base phosphorothioate oligodeoxynucleotide complementary to the messenger RNA of the major immediate-early region proteins of human cytomegalovirus, and is a potent and selective antiviral agent for cytomegalovirus retinitis, a herpes-like eye disease that afflicts the immune-suppressed.
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Phosphorothioate (PS) oligodeoxynucleotides are the ‘first generation’ DNA analogs. The ‘second generation’ ONs contain nucleotides with alkyl modifications at the 2′ position of the ribose. They are less toxic than PS-DNAs and have a slightly enhanced affinity. DNA and RNA analogs with modified phosphate linkages, or different sugar residues substituting the furanose ring have been referred as ‘third generation’ [34]. For instance, peptide nucleic acids and their analogs display superior sequence specificity and are resistant to nuclease degradation. These third generation AS-ON have limited non-specific interactions with other genes and, therefore, have shown great potentials in clinical trials.
Ribozymes
Ribozymes (Rz) are catalytically active ONs that both bind and cleave target RNAs. They were discovered after the AS-ON technology. Initial findings on ribozymes raised the hope that they may offer a more potent alternative to AS-ONs. Many cell based and animal tests have performed on anti-viral effects of ribozymes, including HIV, hepatitis B, hepatitis C, influenza, etc. Results from these tests have shown that ribozymes are promising viral inhibitors [35-38]. However, further progress in the field has been hampered by difficulties to achieve satisfactory potency and efficient intracellular delivery of ribozymes in vivo. HEPTAZYME is a modified ribozyme that cleaves the internal ribosome entry site of the Hepatitis C virus. The Rz was demonstrated to inhibit viral replication up to 90% in cell culture [39]. HEPTAZYME was tested in a Phase II clinical trial, but was later withdrawn from further clinical trials due to insufficient efficacy. So far, there is no anti-viral ribozymes that are being actively tested in advanced clinical trials.