Editorial [Hot Topic: HIV Drug Design (Executive Editor: A.S. Bourinbaiar)]

The need to discover novel means to treat HIV infection remains as critical as ever since the epidemic of AIDS continues to grow unabated. The emergence of resistant virus strains and the toxic side effects of current drugs require new classes of therapeutic agents with better and safer properties. In this issue of "Current Pharmaceutical Design" several authors review their effort of accomplishing this task. Debra Meyer proposes the use of iron chelators as a therapy for AIDS and tuberculosis (TB) since excess iron in the body assists to multiplication of causative pathogens [1]. Chelators in clinical use like desferioxamine, deferiprone, and bleomycin along with others still under development have been shown to inhibit HIV and mycobacterium in vitro. Concurrent infection with HIV and Mycobacterium tuberculosis is common, especially in developing countries, and thus if these chelators are found effective they could become treatment of choice as safe and effective therapy. Pohlmann and Reeves describe inhibitors of HIV entry as promising class of drug candidates [2]. The penetration of HIV into target cells involves interactions of the viral envelope protein (Env) with CD4 and a coreceptor, usually CCR5 or CXCR4. Both, virus receptors and structures in Env associated with membrane fusion are promising targets for therapeutic intervention. Pumfery et al., review inhibitors of cyclin-dependent kinases (CDKs) as key regulators of the cell cycle and RNA polymerase II transcription [3]. Pharmacological CDK inhibitors (PCI) are known as potential cancer therapeutic agents. However, lately they have been shown to display anti-viral activity against several types of viruses. HIV replication appears to be blocked through CDK2 and 9, and cellular co-factors for HIV-1 Tat transactivation. These authors explain inhibitory mechanisms of flavopiridol and CYC202 and discuss their possible use for AIDS therapy. Varier and Kundu bring up recent advances in our understanding of genome-integrated viral gene expression and show that the regulation of chromatin function is closely linked to the replication of HIV [4]. Therefore, they propose a new therapeutic approach by targeting the chromatin-modifying enzymes such as histone acetyltransferases and deacetylases that may lead to new anti-HIV therapeutics. Christopher and Wong discuss the important aspect of delivery of antiviral drugs [5]. Recently, nucleic acid-based drugs have shown promise as anti-viral agents but their therapeutic efficacy is often restricted by limited delivery to intracellular sites of viral replication and by nuclease degradation. Several candidate AIDS drugs from this class including antisense oligonucleotides, siRNAs, ribozymes and DNAzymes are now in development. These authors review their own and research by others on finding means to optimize drug delivery to the desired target cells while eliminating adverse side effects. Bregenholt et al., look at the treatment of HIV and other viral infections from viewpoint of therapeutic antibodies [6]. This type of therapy has become popular in recent years as first commercial antibody preparations became highly successful. They have developed a recombinant technology that allows to use polyclonal instead of monoclonal antibodies. Due to unique design, so-called symphobodies, can be employed against a variety of pathogenic viruses, including vaccinia, smallpox virus, respiratory syncytial virus, and HIV. Finally, Bourinbaiar et al., review therapeutic AIDS vaccines with special emphasis on vaccines which operate according to the principles of alloimmunization [7]. Unlike prophylactic vaccine designed to prevent HIV infection, therapeutic vaccine is given to infected individuals to help fight the disease by modulating their immune response. The results of over sixty therapeutic vaccine trials have consistently shown that while in vitro measured HIVspecific immune responses were evident as a result of vaccination no obvious clinical improvements have been observed. The instances of the apparent clinical benefit, however, were invariably associated with vaccines that contained allo- or auto-antigens. Examples of such vaccines are reviewed in detail. The current strategy in finding effective AIDS therapy needs to be supplemented by research on therapeutic antibodies and vaccines. Taken together, these articles provide a glimpse on the current drug discovery effort in AIDS arena. This information should be of particular interest to seasoned as well as to new investigators in HIV field and may aid in the conceptualization of various strategies aimed at managing this difficult-to-treat disease. 1942 Current Pharmaceutical Design, 2006, Vol. 12, No. 16 HIV Drug Design References [1] Meyer D. Iron chelation as therapy for HIV and Mycobacterium tuberculosis co-infection under conditions of iron overload. Curr Pharm Design 2006; 12(16): 1943-1947. [2] Pumfery A, de la Fuente C, Berro R, Nekhai S, Kashanchi F, Chao S-H. Potential Use of Pharmacological Cyclin-Dependent Kinase Inhibitors as Anti-HIV Therapeutics. Curr Pharm Design 2006; 12(16): 1949-1961. [3] Pöhlmann S, Reeves JD. Cellular entry of HIV: Evaluation of therapeutic targets. Curr Pharm Design 2006; 12(16): 1963-1973. [4] Varier RA, Kundu TK. Chromatin modifications (Acetylation/ Deacetylation/ Methylation) as new targets for HIV therapy. Curr Pharm Design 2006; 12(16): 1975-1993. [5] Christopher ME, Wong JP. Recent developments in delivery of nucleic acid-based antiviral agents. Curr Pharm Design 2006; 12(16): 1995-2006......