Current Topics in Medicinal Chemistry - Volume 3, Issue 13, 2003

The replication cycle of human immunodeficiency virus (HIV) is divided into an early and a late phase. Most of the steps of the cycle have been targeted in antiviral therapy, although the drugs currently available for clinical use are only effective against two replication enzymes of the virus, either against the reverse transcriptase or against the viral protease. The introduction of combination anti-retroviral therapy changed the prognosis of HIV infection. HIV-related morbidity and mortality rates in patients with advanced HIV infection have significantly declined. However, there are severe limits of HAART. Current anti-retroviral therapy do not allow viral eradication, therefore long-term use of the drugs is required. As a consequence, resistance develops in a significant portion of patients. Furthermore, several adverse metabolic side effects have been observed associated with the therapy. Therefore new approaches are required to control or eradicate this deadly virus infection.

The field of antiretroviral therapy has witnessed remarkable progress during the past 15 years. There are now over a dozen approved therapeutic agents for infection with the human immunodeficiency virus (HIV), a pathogen that once caused nearly uniformly fatal illness. These agents usually target two essential enzymes of the virus, the reverse transcriptase and the protease. The era of potent antiretroviral therapy, also termed highly active antiretroviral therapy, began in 1996 and has been marked by dramatic declines in morbidity and mortality due to HIV disease in the developed world. These advances have not been without their cost in terms of drug resistance and toxicity and unwanted effects. Concern about these negative effects has led to a more conservative approach to the timing of the initiation of therapy and to clinical trials of intermittent therapy in an attempt to decrease the total exposure to drugs over time. Immune-based approaches such as therapeutic vaccination may someday permit viremia to be controlled in the absence of drugs. Antiviral potency has been the key to the initial success of drug regimens, as well as to the durability of their success, the restoration of immune function, the prevention of the emergence of resistance, and ultimately the prevention of disease progression. Future progress in antiretroviral therapy will bring more choices for physicians and patients and will make an already complex field both more challenging and more rewarding.

Control of AIDS requires development of special therapeutic strategies in order to reduce the level of monocyte / macrophage HIV infection, to prevent spread of HIV within the monocyte / macrophage reservoir, to maintain a therapeutically effective drug concentration in sanctuaries such as the brain and to overcome the problem of cellular resistance mechanisms. A popular approach towards this end has been the development of prodrugs of anti-HIV drugs. This review covers the different strategies devised for the design of prodrugs of anti-HIV agents with emphasis on the recent findings in this field of research. Thus, prodrugs of nucleoside reverse transcriptase inhibitors (NRTIs) including, 5'-O carboxylic ester derivatives, 5'-O- monophosphate analogues, macromolecular derivatives, prodrugs of purine nucleosides, prodrugs of acyclic nucleosides, homo and hetero dinucleotides, prodrugs of non-classical nucleoside analogues, boranophosphate triesters of NRTIs, and prodrugs of protease inhibitors including acyl-substituted prodrugs, prodrugs with increased water solubility, monophosphate prodrugs, and conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor through spontaneously cleavable linkers, constitute the subject of this review.

Replication of human immunodeficiency virus 1 (HIV-1) uses a viral reverse transcriptase (RT) to convert its positive-strand RNA into double stranded DNA, which is then integrated into host genome. Reverse transcription is a complex event involving p66 and p51 RT subunits but also several viral proteins including Nef, Tat, Vif, IN, NCp7 and p55gag. Viral RNA itself forms a primer / template complex by association with a cellular tRNALys3 which is already present in mature virions. A RT initiation complex (RTIC) is thus formed which may also involve cellular protein upon viral entry. X rays diffraction and NMR studies of free or inhibitor-bound RT have led to the recognition of RT 3D structure, and allowed a thorough understanding of the mode of action of classical competitive nucleoside RT inhibitors (NRTIs) and of the binding of allosteric, non NRTIs (NNRTIs) inhibitors. This also opened an access to computer-aided drug design and modeling. Current NNRTIs represent, in terms of chemical structures, a heterogeneous class of inhibitors currently undergoing extensive development. By contrast with NRTIs, they seem to block initiation steps of reverse transcription. Molecular dynamics, detailed analysis of their interaction with RT as well as the incidence, in the series, of cases of non classical biological behavior, as illustrated here for a new family of compounds, suggest mechanisms of action which are not understandable without considering the involvement of the RTIC as a whole. This opens the exciting perspective of developing new compounds based on this integrated knowledge.

In order to combat the human immunodeficiency virus (HIV), diverse strategies have been developed to research on compounds which can be developed as therapeutic agents. Screening of natural products derived from numerous species has afforded metabolites with significant antiviral activity against the HIV. The marine environment representing approximately half of the global biodiversity offers an enormous resource for novel compounds. Currently more than 150 natural products with promising levels of anti-HIV activity have been isolated following bioassay guided protocols from aqueous or organic extracts of marine organisms. Some of the most characteristic marinemetabolites that have exhibited significant anti-HIV activity on different biochemical assays designed for chemotherapeutic strategies are: Cyanovirin-N, a protein from a blue green alga; various sulfated polysaccharides extracted from seaweeds (i.e. Nothogenia fastigiata, Aghardhiella tenera); the peptides tachyplesin and polyphemusin, which are highly abundant in hemocyte debris of the horseshoe crabs Tachypleus tridentatus and Limulus polyphemus; sponge metabolites such as avarol, avarone, ilimaquinone and several phloroglucinols; and a number of metabolites from marine fungi such as equisetin, phomasetin and integric acid. Considering that number of unique metabolites that have been isolated from a small extent of the ocean's biological and chemical diversity, the oceans represent a virtually untapped resource for the discovery of novel bioactive compounds.

Antiretroviral therapy with potent combinations of drugs has been responsible for a significant decline in the occurrences of AIDS defining conditions and death in the developed world. However, therapy requires lifelong use and is complicated by relatively high failure rates, significant toxicities, adherence difficulties and the development of resistance. The combination of these complications of therapy and the availability of this treatment to only 1 in 20 of the estimated 34 million people infected world wide has prompted us to reconsider the current strategies for achieving the goals of HIV therapy. A more rational approach to therapeutic interactions is needed, particularly with respect to therapy in the developing world, with the focus shifted towards maintaining relative viral control over the long term. One potential mechanism to attain viral control over the long term is the use of therapeutic vaccines. This chapter will review the scientific rationale for therapeutic HIV-1 vaccines and the vaccines that have been evaluated as a therapeutic to date including recombinant envelope glycoproteins, inactivated envelope depletd virus, regulatory proteins such as Tat, cytokines such as IFN-α, DNA vaccines, and live viral vectors. Although the future role of therapeutic vaccines in the treatment of HIV-1 remains to be determined, at a minimum this immunomodulatory approach will provide new insights into fundamental viral-host cell interactions and the pathogenesis of HIV-1. Yet even more notable, is that, if successful, a therapeutic vaccine product would be inexpensive and rapidly exportable representing a treatment strategy for people living with HIV infection worldwide.