Drug Design for HIV Background about HIV The human immunodeficiency virus (HIV) was first discovered in 1985.HIV is most commonly transmitted by sexual contact and needle-sharing due to the exchange of body fluids like blood and semen. The virus damages the body’s immune system resulting in AIDS (acquired immune deficiency syndrome). A worldwide epidemic, 39.5 million individuals were infected with HIV/AIDS in 2006. In the same year, 2.9 million deaths were attributed to AIDS (Cichocki, 2008). HIV is a retrovirus, which store their genetic information as RNA instead of DNA. HIV enters human immune system CD4 cells through specific receptors in its viral coat. Inside the cell, the HIV reverse transcriptase converts the viral RNA into DNA. this DNA is transported into the cell nucleus where it is inserted into the human genome by the HIV integrase enzyme. The HIV DNA may lie dormant, but is later expressed for the synthesis of new HIV proteins and enzymes. The HIV protease is active at this stage of the life cycle where its role is to cut long protein strands to form viral cores. The development of the pathogenic effects of HIV is characterized by the interaction between viral and host factors. A broad spectrum of antiviral strategies was developed for each step of the viral replication cycle. Every stage in the life cycle, and every gene product of HIV is a potential target. Host proteins that are recognized to have an essential role in the viral life cycle are also targets of HIV therapy (Nielsen, Pedersen, amp. Kjems, 2005). As of 2007, more than 20 anti-HIV drugs have been approved (De Clerq, 2007). The drugs block the enzyme activity of any of the enzyme that HIV needs to replicate inside host cells: reverse transcriptase, protease, fusion inhibitors, and lately integrase inhibitors. The norm is to utilize highly active antiretroviral therapy (HAART), which combines two or three drugs to overcome the development of drug resistant targets. Nevertheless, multi-drug resistant HIV continue to develop due to the high viral mutation rates. Choice of Drug TargetIntegrase is the chosen target for the drug to be designed for HIV treatment. it facilitates the insertion of the double-stranded DNA copy of the HIV RNA genome into the host genome, an absolute requirement for viral replication (LaFemina, et al., 1992). Integration of the HIV DNA requires 3 processing of the final two bases of the viral DNA long terminal repeat (LTR), and DNA strand transfer activity. HIV integrase was found to be composed of several multimers with functional domains sufficient for 3 processing and DNA strand transfer (Engelman, Bushman, amp. Craigie, 1993). The integrase positions the two 3-hydroxyls of its LTRs for nucleophilic attack on the phosphodiester bonds and insertion into the genomic DNA. Gln 148, found in the active site of integrase, was found to have a pivotal role in assembly, strand transfer catalysis, and inhibitor binding (Dicker, et al., 2007).Proposed Drug DesignsIntegrase is an ideal target because it has no known homolog in humans, and therefore strategies can be designed that solely act on it. The designs, which can target the HIV integrase, should consider the known mechanisms for insertion of the viral DNA into the host genome. The catalytic function of integrase can be blocked by inactivating or introducing conformational changes to its binding sites within the viral DNA. Alternatively, the active site of the enzyme or its binding domain can be altered by introducing changes into its structure (Nielsen, Pedersen, amp. Kjems, 2005). Inhibitory molecules can be oligonucleotides, dinucleotides, and chemical agents (Nair, 2002). The integrase binding site in the LTR region contains the 5-GGAAGGG-3, which can be targeted by oligonucleotide conjugates that complex with the viral DNA and block the catalytic functions of the integrase (Nair, 2002). Some nucleotides also inhibit the integrase by interacting with the catalytic domain. To determine which compound can work best in inactivating integrase, it is necessary to understand the molecular structure in relation to the catalytic activity of the integrase enzyme. From this, compounds with known molecular structure, or even natural products, can be screened and evaluated in the presence of the integrase, under in vitro conditions. It is only necessary to determine the loss of activity of integrase through spectrophotometric means or by the formation of precipitates (in the case of complex formation). Biochemical studies need to be validated by in vivo experiments after suitable compounds have been selected and characterized. ReferencesCichocki, M 2008, ‘HIV statistics – AIDS data – estimates of the worlds HIV epidemic’, Retrieved March 3, 2009, from About.com:HIV/AIDS: http://aids.about.com/od/dataandstatistics/qt/ worldstats.htm.De Clerq, E 2007, ‘The design of drugs for HIV and HCV’, Nature Reviews, vol. 6, pp. 1001-1018.Dicker, I, Samanta, H, Li, Z, Hong, Y, Tian, Y, Banville, J, Remillard, R, Walker, MA, Langley, DR amp. Krystal, M 2007, ‘Changes to the HIV long terminal repeat and to HIV integrase differentially impact HIV integrase assembly, activity, and the binding of strand transfer inhibitors’, Journal of Biological Chemistry, vol.282, no. 43, pp. 31186-31196.Engelman, A, Bushman, F amp. Craigie, R 1993, ‘Identification of discrete functional domains of HIV-1 integrase and their organization within an active multimeric complex’, EMBO Journal, vol. 12, no. 8, pp. 3269-3275.Havlir, D 2008, ‘HIV integrase inhibitors- out of the pipeline and intothe clinic’, New Engalnd Journal of Medicine, vol. 359, no. 4, pp. 416- 418.LaFemina, R, Schneider, C, Robbins, H, Callahan, P, LeGrow, K, Roth, E, Schleif, WA amp. Emini, EA, 1992, ‘Requirement of active human immunodeficiency virus type 1 integrase enzyme for productive infection of human T-lymphoid cells’, Journal of Virology, vol. 66, no. 12, pp. 7414-7419.Nair, V 2002, ‘HIV integrase as a target for antiviral chemotherapy’, Review of Medical Virology, vol. 12, pp. 179-203.Nielsen, M, Pedersen, F amp. Kjems, J 2005, ‘Molecular strategies to inhibit HIV-1 replication’, Retrovirology, vol.2, pp. 10.