Current Topics in Medicinal Chemistry - Volume 4, Issue 9, 2004

Human immunodeficiency virus type 1 (HIV-1) gene expression and transcription is an essential step in the viral life cycle, which is considered to be a possible target for inhibition of HIV-1 replication. Among the factors involved in this step, the cellular transcription factor nuclear factor (NF)-kB is the most potent inducer of HIV-1 gene expression, while the viral transactivator protein Tat seems to play a central role in sustaining a hi Read More

The chemokine receptors CXCR4 and CCR5 are used as the main co-receptors by the T-cell-tropic (CXCR4-dependent, X4) and macrophage-tropic (CCR5-dependent, R5) HIV-1 strains, respectively, for entering their target cells. The natural ligands for CXCR4, the CXCchemokine SDF-1 and CCR5, the CC-chemokines RANTES, MIP-1a and MIP-1β are described to inhibit viral entry. In this review we focus on chemokine receptor / HIV Read More

The development of novel compounds that can effectively inhibit both wild type and the most consensus resistant strains of human immunodeficiency virus type 1 (HIV-1) is the primary focus in HIV disease management. Combination therapy, comprising at least three classes of drugs, has become the standard of care for acquired immunodeficiency syndrome (AIDS) or HIV-infected individuals. The drug cocktail c Read More

Almost fifteen years ago, the first non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) lead compounds have been discovered. Nowadays, three NNRTIs are approved for treatment of HIV-1-infected individuals and several others are subject of (advanced) clinical trials. Although the NNRTIs target HIV-1 RT, they are clearly different from the nucleoside RT inhibitors (NRTIs). They are highly selective for HIV-1 and do no Read More

Emergence of drug-resistant viral strains is one of the major milestones and the main cause for the failure of antiretroviral therapy. Combination of different anti-HIV agents has become the standard clinical practice to keep the viral load at low or even undetectable levels and to prevent emergence of virus-drug resistance. Among the human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitors, the so called Read More

HIV-1 integrase is a multidomain enzyme which is required for the integration of viral DNA into the host genome. It is one of three enzymes of HIV, the others being the Reverse Transcriptase and the Protease. It is an attractive target for therapeutic drug design. The enzyme consists of three domains. The N-terminal domain has a His2Cys2 motif which chelates zinc, the core domain has the catalytic DDE motif which is require Read More

Since the beginning of the HIV epidemic almost 70 million people have been infected with HIV. It is estimated that 42 million people are currently living with HIV/AIDS. The spread of HIV continues throughout the world and current estimates indicate that in 2002, 5 million people were newly infected with HIV and 3 million people died. Current treatments employ a combination of therapeutic agents that target the viral reverse Read More

The identification of HIV-1 protease (HIVp) as a target for therapeutic intervention against AIDS was soon followed by major efforts to understand its substrate specificity, reaction kinetics and three-dimensional structure, both in the free state and in complex with a number of ligands including substrate mimics, products, and inhibitors. On the whole these studies have been extremely successful and have had a major impact on Read More

Macrophages (M / M) are identified as the second cellular target of HIV and a crucial virus reservoir. M / M are persistently infected cells and not susceptible to the HIV cytophatic effects typical of infected CD4+ T-lymphocytes. HIV replication in M / M is a crucial pathogenetic event during the whole course of the disease. Moreover, the dynamics of HIV-1 replication and cumulative virus production is quite different in M / M and Read More