Current Medicinal Chemistry - Anti-Infective Agents - Volume 1, Issue 2, 2002

Human immunodeficiency virus (HIV) and Hepatitis B virus (HBV) present extreme health threats worldwide. Although there are approved drugs for both infections, they have significant limitations including toxicities associated with chronic administration, complex dosing regimens, pharmacokinetic interactions and the development of resistance. These limitations are driving the continued search for new agents with improved clinical profiles. A key target for therapeutic intervention for both viruses are the virally encoded polymerases. The HIV RNA directed DNA polymerase (reverse transcriptase, RT) has been extensively studied. The HBV polymerase has not been successfully cloned expressed and purified. Consequently detailed enzymatic / structural analysis has not been carried out. However, high primary sequence homology and functional similarity between HIV RT and HBV polymerase suggest that HIV RT can serve as a model for the study of the HBV encoded enzyme. HIV RT catalyzes the synthesis of double stranded viral DNA using genomic RNA as a template by a bireactant-biproduct mechanism. In this mechanism, the RT, the primed genomic RNA (template) and a natural 2'-deoxynucleotide (dNTP) substrate form a ternary complex. The molecular forces that direct the affinity and specificity of the binding, and the reactivity of the nucleic acid templates and dNTP substrates were studied extensively using biophysical, kinetic, and solid state X-ray techniques. The results of these studies are reviewed here and discussed in the context of the opportunity they offer for establishing structure-activity relationships to direct the design of a new generation of antiviral agents with better clinical and resistance profiles.

This non-nucleoside reverse transcriptase inhibitor review covers the patent and published literature from January, 1998-August, 2001. Major advances have been made in the past decade in discovering non-nucleoside reverse transcriptase inhibitors that are effective in inhibiting replication of wild-type virus. Attention is now focused upon the discovery of agents that are effective in inhibiting replication of virus' with singly and doubly mutated HIV-1 reverse transcriptase. Notable advances in the discovery of such broad spectrum therapeutics are SG-153 and the quinazolines DPC961 and DPC083. Attempts at discovering other broad spectrum anti-viral agents are presented herein.

Inhibitors of HIV protease have been key components of highly active retroviral therapy, which is credited with dramatically reducing the mortality and morbidity associated with HIV infection. Nevertheless, currently available therapies are insufficiently effective in a significant proportion of infected patients; furthermore, even successful therapy may prove to be of limited durability over time. In particular, the emergence of highly resistant viral strains presents a serious threat to continued success in treatment of AIDS. Patient noncompliance, exacerbated by complex dosing schedules and unpleasant side effects, not only compromises efficaciousness but also contributes to emerging resistance. For these reasons it is necessary to continue bringing to market new agents which show greater potency against resistant mutants, as well as decreased toxicity and more favorable pharmacokinetic properties which should lead to improved patient compliance. This paper summarizes recent developments in HIV protease research, with emphasis on compounds or structural classes which may show promise for clinical development.

The hepatitis C virus infects an estimated 1-3% of the world population. A large proportion of individuals afflicted by this rapidly spreading epidemic eventually progress to chronic liver disorders. Liver failures associated with chronic hepatitis C infections are the leading cause for liver transplantations in the US. Currently, the backbone of anti-HCV therapy, consisting of various forms of interferon in combination with broad-spectrum antivirals such as ribavirin, has only met with limited success. This review will provide coverage of recent efforts towards the development of novel antiviral strategies that target inhibition of essential enzymatic functions encoded by the non-structural region of the HCV genome. These include principally, inhibition of the NS3 protease and helicase, and of the NS5B RNA-dependent RNA polymerase.

The human cytomegalovirus (HCMV) is a highly prevalent member of the herpesvirus family responsible for opportunistic infections in immunocompromised individuals such as organ transplant recipients, AIDS patients and newborn infants. The advent of HAART as an effective control for AIDS has reduced the demand for anti-HCMV drugs in AIDS patients, but HCMV remains a significant challenge in organ transplant therapy. As resistance to HAART emerges, HCMV has the potential to become a significant risk for those infected with HIV. Existing chemotherapies for the treatment of HCMV infections suffer from toxicity, poor bioavailability and tolerability. These drugs also do not clear the virus.A number of strategies have been employed to find new therapeutic agents. Non-nucleoside inhibitors of HCMV are reviewed in the present paper. These compounds inhibit viral growth by interfering with viral molecular functions and also by intercepting host cell processes. General classes of potential drugs discussed include HCMV protease inhibitors, compounds preventing viral DNA replication and materials with unknown mechanisms of action. Natural products, rationally resigned inhibitors and compounds found by high throughput methods are described.