Current Pharmaceutical Design - Volume 9, Issue 22, 2003

The selection of topics and authors was made with the intention to complement the first issue of anti-HIV Drug Design (Current Pharmaceutical Design, 2002, Volume 8, number 8). These articles present alternative approaches other than available chemotherapeutic agents against Human Immunodeficiency Virus (HIV). Several HIV protease inhibitors (PIs) show suboptimal pharmacological and pharmacokinetics properties such as low oral bioavailability and water solubility, rapid metabolism, and / or low level of penetration into lymphatic and central nervous systems. The article by Vierling and Grenier [1] will focus on the potential prodrug approaches of HIV PIs, including “lipophilic”, “hydrophilic”, “active transport” and “double-drug prodrug” to improve or modify the physicochemical and pharmacokinetics properties of the parent PIs. Fosamprenavir, a hydrophilic phosphate ester of amprenavir, which has reached the phase III clinical trials, is discussed as a promising prodrug. After two decades of the emergence of Acquired Immunodeficiency Syndrome (AIDS), the development of an effective vaccine has been hampered by the major obstacles such as viral spike formation, envelope heavy glycosylation, HIV rapid mutation, and conformational switch of HIV gp proteins. The review by Lai-Xi Wang [2] provides a comprehensive overview of these obstacles and recent approaches toward developing a neutralizing antibody-based HIV vaccine. Integrase (IN) is an essential enzyme in the life cycle of HIV and has been considered as a potential target for developing and design of HIV inhibitors. Dayam and Neamati [3] review potential small molecule compounds which have been reported to inhibit recombinant HIV-1 IN during the past two years. These compounds include natural products, synthetic hydroxylated aromatics, peptides, sulfates, sulfonates, nucleotides, mechanism-based inhibitors, and diketoacid-containing inhibitors. Proteolytic events occur at many stages of HIV life-cycle. These events can be considered as targets for developing chemotherapeutic agents against HIV-1 replication. Tözser and Oroszlan [4] discuss events such as the early-phase of HIV replication, ubiquitin-dependent proteolytic degradation of the unfolded viral proteins, the envelope protein processing, and potential approaches for targeting these events. The quantitative structure-activity relationships (QSAR) have been used to correlate the anti-HIV activities of several analogs with physicochemical properties and molecular descriptors. Douali and his colleagues [5] discuss the application of neural networks for the prediction of anti-HIV activity of HEPT derivatives. All the above reviews will provide an update for researchers on current progress in this area and will be use of scientists planning to enter the field. I deeply appreciate the excellent contributions from all of the authors. Without their dedication, the publication of this issue would not have been possible. References [1] Vierling P, Grenier J. Prodrugs of HIV Protease Inhibitors. Curr Pharm Des 2003; 9(22): 1755-1770. [2] Wang L.-X. Bioorganic Approaches towards HIV Vaccine Design. Curr Pharm Des 2003; 9(22): 1771-1787. [3] Dayam R, Neamati N. Small-molecule HIV-1 Integrase Inhibitors: the 2001-2002 Update. Curr Pharm Des 2003; 9(22): 1789-1802. [4] Tozser J, Oroszlam S. Proteolytic Events of HIV-1 Replication as Targets for Therapeutic Intervention. Curr Pharm Des 2003; 9(22): 1803-1815. [5] Douali L, Villemin D, Cherqaoui D. Comparative QSAR Based on Neural Networks for the Anti-HIV Activity of HEPT. Curr Pharm Des 2003; 9(22): 1817-1826.

Despite the efficiency of the present polytherapies against AIDS, HIV replication continues indicating difficulties in drug adherence, drug-drug interactions, resistance issues, and the existence of reservoirs or sanctuaries for the virus. Moreover, most of the current FDA-approved HIV protease inhibitors (PIs) display disadvantageous physicochemical and pharmacological properties such as low water solubility, low oral bioavailability and / or low level of penetration into the HIV sanctuaries resulting from their in vivo binding to the plasma proteins and to the Multi-Drug-Resistant P-glycoprotein, their rapid metabolization and inactivation by the liver cytochrome P450 enzymes. To overcome these suboptimal pharmacokinetics, high daily doses must be ingested, which complicate patient adherence to the prescribed regimen and contribute to the appearance of serious long-term metabolic complications and to the decrease of the viral treatment outcome. Another attractive alternative aimed at improving the safety, pharmacokinetics, and therapeutic potency of the current PIs is to modify these PIs into pharmacologically inactive prodrugs which are converted in vivo into their parent active drug. The present review is dedicated to the different prodrug approaches, including the “lipophilic”, “hydrophilic”, “active transport” and “double-drug” prodrug strategies, which have been applied more particularly to the current HIV PIs used in clinic. Among the strategies explored up to now, the most successful one was the “hydrophilic” prodrug approach which has led to the discovery of fosamprenavir, a phosphate ester prodrug of amprenavir, which has reached phase III clinical trials. This success gives strong support for the search of PI prodrugs as a therapeutic alternative in addition to the development of new and well-tolerated PIs.

The worldwide epidemic of HIV / AIDS urges the development of an effective vaccine. With the identification of HIV as the cause of AIDS about two decades ago, it was once expected that a preventive vaccine would follow closely behind. But the early promise of HIV envelope gp120 as a preventive vaccine was not fulfilled. Broadly neutralizing antibodies and HIV-specific cytotoxic T lymphocytes (CTL) are two immune effectors that an effective HIV vaccine may have to elicit. Experiments in animal models have proved that sufficient levels of neutralizing antibodies can clean up the virus and protect the animals from viral challenge. Therefore, the induction of a broadly neutralizing antibody response remains a principal goal in HIV vaccine development. To achieve persistent infection, HIV has evolved elegant strategies to evade host immune surveillance. These include envelope oligomerization, rapid mutation, heavy glycosylation, and conformational changes. Each level of the HIV's defenses provides an additional dimension of complexity that has to be taken into account in order to come up with a vaccine conferring strong and long lasting immunity. Important progresses have been made in recent years in understanding the structure of HIV envelopes and the molecular mechanism of HIV evasion to the immune system. This in turn has greatly facilitated a rational design of immunogens capable of eliciting broadly neutralizing antibodies against HIV. The present review provides an overview of the major scientific obstacles we are facing in the development of an effective HIV vaccine, and discusses recent progresses in the field with a focus on current approaches toward a neutralizing antibody-based HIV vaccine. The bioorganic aspects of the approaches are emphasized.

Integration of viral DNA into host cell chromosomal DNA to form a provirus is an essential step in the viral life cycle. This process is mediated by integrase (IN), a 32 KDa viral enzyme. The unique properties of IN makes it an ideal target for drug design. First, there are no cellular homologues to IN and the reactions catalyzed by IN are unique. Second, IN is absolutely required for viral replication and mutations in a number of key residues dramatically block viral replication. Third, IN has been validated as a legitimate target and the results from S-1360 (1) the only available IN inhibitor under clinical trials suggest synergistic effect with reverse transcriptase (RT) and protease (PR) inhibitors. During the past 10 years a plethora of inhibitors have been identified and some were shown to be selective against IN and block viral replication. The two most predominant classes of inhibitors have been the catechol containing hydroxylated aromatics and more recently the diketoacid containing aromatics. Herein, we review all small molecule compounds reported to inhibit recombinant HIV-1 IN with IC50 values ≤ 20 μM during the past two years. It is important to bear in mind that the true mechanism of action and antiviral activities of many of the compounds are currently not established. However, based on the growing body of literature certain classes of compounds can be easily excluded as bona fide IN inhibitors.

Acquired immunodeficiency syndrome (AIDS) is a worldwide epidemic caused by infection with HIV, a human retrovirus. Proteolysis occurs at many points of the retroviral life-cycle, and these events can be considered as targets for chemotherapy. The most well-known proteolytic action in the retroviral life-cycle is the processing of the Gag and Gag-Pro-Pol polyproteins with the virally encoded protease at the late phase of viral infection. Protease inhibitors, together with reverse transcriptase inhibitors, are important components of the drug combinations currently used to treat HIV patients. The current combination therapy substantially reduced morbidity and mortality in HIV-infected patients. However, these drugs do not allow viral eradication, therefore their long-term use is required, allowing the development of resistance in a large portion of patients. Furthermore, several adverse metabolic side effects have been observed associated with the therapy. Thus, new approaches are required to eradicate HIV infection, which may include targeting of the potential early-phase function of the viral protease, and other crucial proteolytic events of the viral replication, such as the ubiquitin-dependent proteolytic degradation of the unfolded viral proteins as well as the inhibition of envelope protein processing.

Among the non-nucleoside reverse transcriptase inhibitors, 1-[2-hydroxyethoxy-methyl]-6-(phenylthio) thymine (HEPT) derivatives have proved to be potent and selective inhibitors of human immunodeficiency virus (HIV-1). They are able to completely suppress virus replication in cell cultures. The quantitative structure-activity relationships (QSAR) try to describe the association between biological activities of a group of congeners and their molecular descriptors. In this paper, recent works on the application of neural networks (NN) and multiple regression analyses to quantitative structure-anti-HIV activity of HEPT derivatives are reviewed. NN have their origins in efforts to reproduce computer models of the information processing that takes place in the brain. They have found application in a wide variety of fields, such as image analysis of facial features, stock market predictions, etc. Application of the NN methods to problems in chemistry and biochemistry has rapidly gained popularity in recent years. We briefly describe a methodology for designing NN for QSAR and estimating their performances, and apply this approach to the prediction of anti-HIV activity of HEPT. The predictive power of the NN used is compared with that of other statistical methods.