Antiviral chemotherapy

De Clercq E, Eield H J (2006) Antiviral prodrugs - the development of successful prodrug strategies for antiviral chemotherapy. Brit J Pharmacol 147 1-11 De Clercq E, Hol A, Rosenberg I, Sakuma T, Balzarini J, Maudgal PC (1986) A novel selective broad-spectrum anti-DNA virus agent. Nature 323 464 67 De Clercq E, Sakuma T, Baba M, Pauwels R, Balzarini J, Rosenberg I, Hol A (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res 8 261-272... 

Helicase has also been a focal point for the development of antiviral chemotherapy of the coronavirus associated with severe acute respiratory syndrome (SARS) in humans. Although several experimental compounds with nucleic acid binding activity showing effective inhibition of SARS-CoV helicase were reported in 2005, there have been no reports of any further development since that time (Kesel 2005). It remains to be seen whether the S ARS-CoV compounds will be developed further, especially since no new infections have been observed in recent years. 

The identification of inhibitors of virus subunit assembly has been an objective of virologists for several years but it is only recently that papers have been published that demonstrate the validity of this approach to antiviral chemotherapy. It is hoped that the information provided by the compounds described above will provide the foundation for the generation of potent antiviral drugs to combat diseases caused by HIV, HBV and other viruses. 

Bogner E (2002) Human cytomegalovirus terminase as a target for antiviral chemotherapy. Rev Med Virol 12 115-127... 

Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan... 

To determine if the high in vitro potents of the anti-HIV compound 30 translates into antiviral efficiency in vivo, Datema et al. investigated the inhibition of HIV-1 production and of depletion of human T cells in HIV-1-infected SCID-hu Thy/Liv mice [37]. Steady levels of 100 ng of 30 or higher per mL in plasma resulted in significant inhibition of HIV p24 protein formation. Daily injection of 30 caused a dose-dependent decrease in viral p24 production, and this inhibition could be potentiated by coadministration of AZT (or DDI). This study suggested that 30 alone or in combination with the licensed anti-HIV agents AZT and DDI may decrease the virus load in HIV-infected patients and, by extension, that the infectious cell entry step is a valid target for antiviral chemotherapy of HIV disease. 

Three basic approaches are used to control viral diseases vaccination, antiviral chemotherapy, and stimulation of host resistance mechanisms. Vaccination has been used successfully to prevent measles, rubella, mumps, poliomyelitis, yellow fever, smallpox, chickenpox, and hepatitis B. Unfortunately, the usefulness of vaccines appears to be limited when many stereotypes are involved (e.g., rhinoviruses, HIV). Furthermore, vaccines have little or no use once the infection has been established because they cannot prevent the spread of active infections within the host. Passive immunization with human immune globulin, equine antiserum, or antiserum from vaccinated humans can be used to assist the body s own defense mechanisms. Intramuscular preparations of immune globulin may be used to prevent infection following viral exposure and as replacement therapy in individuals with antibody deficiencies. Peak plasma concentrations of intramuscular immune globulins occur in about 2 days. In contrast, intravenously administered immune globulin provides immediate passive immunity. 

Nucleoside analogs that have been modified in the sugar portion of the nucleoside can be used to block DNA chain growth. They are useful in anticancer and antiviral chemotherapy. 

Persistent viral infection is a difficult challenge for antiviral chemotherapy. Retroviruses as a class are often found to be responsible for persistent viral infections. Retroviruses are unique RNA viruses characterized by the transcription of their single-stranded RNA into the double-stranded DNA of the host cell using the viral enzyme reverse transcriptase. AIDS is an example of such a persistent and latent human viral infection. 

Declercq. E. and D.J. Jeffries Antiviral Chemotherapy. John Wiley Sons, Inc., New York. NY. 1995. 

Of special interest, because of its biological significance, is the transport of carboxylates and phosphates. In particular, the transport of nucleotides has been achieved [6.28-6.32] and may be made selective by introduction of additional base pairing interactions [6.31,6.32]. The transport of ATP has significance with respect to bioenergetic processes. Antiviral chemotherapy may take advantage of enhancing the cellular uptake of modified nucleotides by carrier species. 

HCMV, a p-herpesvirus, is an opportunistic pathogen in immunocompromised individuals such as AIDS patients and organ transplant recipients [411]. Thus HCMV protease has become a viable target for antiviral chemotherapy [412, 413]. 

Although vaccines exist for many serious viral infections, some drawbacks still exist. Some vaccines are only partially effective, and viral infection still occurs in a significant percentage of vaccinated individuals. Other vaccines, especially killed vaccines, often require periodic readministration (boosters) to help maintain antiviral immunity. In addition, certain types of viruses still lack an effective vaccination. For example, no vaccine is currently approved for the HIV that causes AIDS.51,98 Hence, the improvement of existing vaccines and the development of new vaccines remain two of the more important aspects of antiviral chemotherapy.4... 

Research in antiviral chemotherapy began in the early 1950s, when the search for anticancer drugs generated several new compounds capable of inhibiting viral DNA synthesis. The two first-generation antivirals, 5-iododeoxyuridine and trifluorothymidine, had poor specificity (ie, they inhibited host cellular as well as viral DNA) that rendered them too toxic for systemic use. However, both are effective when used topically for the treatment of herpes keratitis. 

Human cytomegalovirus (HCMV) disease is the most common life-threatening opportunistic viral infection in the inmunocompromised. HCMV protease, a serine protease, plays a critical role in capsid assembly and viral maturation and is an attractive target for antiviral chemotherapy. Slater et al investigated the interaction of various 1,4-naphthoquinones derivatives with HCMV protease. They identified potent irreversible naphthoquinones inhibitors of HCMV protease which covalently modify... 

Couch RB, Six HR (1986) In Mills J, Corey L (eds) Antiviral Chemotherapy New Direction for Clinical Application and Research. Elsevier Science Publishing, Oxford, p. 50... 

Ocular antiviral chemotherapy in the horse is adapted from that used in herpes simplex virus (HSV) and varicella zoster keratitis in humans. The agents used are nucleotide analogs capable of inhibiting viral replication by competitive inhibition of the uptake of the nucleotide into the viral genome. These agents are virustatic and require an intact immune system to suppress or eliminate the virus from the eye. They probably do not eradicate any latent infection. The antiviral drugs available currently do not penetrate intact comeal epithelium and are poorly disseminated within the comeal stroma. The availability of these dmgs will vary in different countries and some may only be obtained from hospital pharmacies. 

With the increase in understanding of viral replication and in particular viral protein and nucleic acid synthesis, and the development of reliable and sophisticated antiviral assays, the young science of antiviral chemotherapy has progressed tremendously over the last 50 years. Acyclovir (Fig. 5.9) was probably the first truly effective and selective... 

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