Preface [Hot Topic: Anti - HIV Design (Executive Editor : K. Parang)].

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.