ABSTRACT
Current medical approaches to viral diseases encompass vaccines, antibodies, and antiviral chemotherapeutic agents. However, many viral diseases lack effective vaccines (e.g., HIV/AIDS, HCV),1-5 or in the case of inŽuenza A, vaccines suffer from incomplete coverage of all viruses due to antigenic drift and antigenic shift.6,7 Similarly, many viral diseases lack effective antiviral drugs.8,9 Nonetheless, antiviral drugs have shown ef‡cacy for certain viral diseases, as both prophylactic and therapeutic agents, and this ef‡cacy has established the importance of antiviral drugs in the absence of vaccines.8-10 In addition, antiviral therapeutics can be used as adjuncts to vaccines.11,12
In general, the current antiviral therapies suffer from limited ef‡cacy, incomplete coverage due to genetic heterogeneity of the virus, rapid emergence of virulent, readily transmissible, drug-resistant mutants, and side effects. This has led to the use of combination antiviral drug regimens to overcome these de‡ciencies in ef‡cacy and to limit development of drug-resistant mutants.13,14 While combination drug therapy has shown increased ef‡- cacy, there remains a signi‡cant unmet medical need for effective, novel, and safe drugs. Equally importantly, there are a number of viruses for which there are no therapeutic agents, even ones with limited ef‡cacy.8,9
There are a number of stages in the viral life cycle that represent potential targets for the development of antiviral therapies: (1) viral attachment and entry into the cell, (2) uncoating of the virus, (3) transcription of viral mRNA, (4) translation of viral mRNA, (5) replication of viral DNA or RNA, (6) maturation of viral proteins, (7) assembly of
CONTENTS
7.1 Introduction ........................................................................................................................ 141 7.2 What Is a Nanoviricide? .................................................................................................... 144 7.3 Evaluation of Nanoviricides in a Rabbit Model of EKC ............................................... 147 7.4 Evaluation of Nanoviricides in a SCID-hu Thy/Liv Model of HIV-1 Infection ........ 149 7.5 Additional Properties ........................................................................................................ 152 7.6 Summary ............................................................................................................................. 152 References ..................................................................................................................................... 153
viral particles, and (8) budding or release of mature virus. The current antiviral drugs approved by the U.S. FDA and international regulatory agencies exploit many of these targets as their mechanisms of action. As depicted in Figure 7.1, there are a number of mechanisms by which antiviral agents can inhibit viral infection, replication, and maturation and release. Table 7.1 summarizes many of the currently available antiviral
TABLE 7.1
Antiviral Therapeutic Targets
therapeutics and their mechanisms of action; it is not meant to be exhaustive but simply to provide examples. Most of the current antiviral strategies are based on inhibition or modulation of the intracellular biochemical pathways, mediated by both viral and host cell enzymes for the production of new virus particles. For example, in the case of HIV, (1) HIV binds to speci‡c cell surface receptors that are required for viral entry into the cell, (2) the viral genomic RNA (v-RNA) is copied into a complementary DNA molecule (v-cDNA) by the viral reverse transcriptase (v-RT), (3) an enzyme called integrase (v-I) inserts copies of the v-cDNA into the nuclear DNA of the cell, (4) this DNA is copied by the cell machinery to make viral messenger RNA (v-mRNA), and is also copied to make new viral genomic RNA (v-RNA), (5) the v-mRNAs are then translated by the cell to make viral precursor proteins, (6) the precursor proteins are processed by the viral protease (v-P) to form mature viral proteins, and (7) the resulting mature viral proteins and two copies of the newly made viral genomic RNA self-assemble, possibly with assistance from both viral-encoded and host machinery factors, such as molecular chaperones, into new virus particles and are released from the cell by budding.15
