For those aged 25-44, HIV dropped from the leading cause of death in 1995 to third and fifth leading causes of death in 1996 and 1997 respectively. The age-adjusted HIV death rate of 5.9 deaths per 100,000 is the lowest rate since 1987; the first year mortality data were available for the disease. This dramatic reduction in AIDS related deaths has largely been due to the advent of anti-retroviral agents which prolong AIDS-free HIV infection as well as life-expectancy once AIDS has developed. Despite the success of HIV therapies, there is still a demand for molecules with reduced toxicity and susceptibility to drug resistance. Early HIV therapies have targeted proteases and reverse transcriptase, both of which are crucial viral proteins. The retroviral encoded protein integrase is required for the insertion of the human immunodeficiency virus type 1 proviral DNA into the host genome. Like proteases and reverse transcriptase, integrase also plays a vital role in the retroviral life cycle, which makes this enzyme an attractive target for the development of new anti-AIDS agents. However, very few inhibitors have been described and none seems to have a potential use in anti-HIV therapy. To obtain potent and specific integrase inhibitors, a group of French researchers have used the two-hybrid system to isolate short peptides. Using HIV-1 integrase as a bait and a yeast genomic library as the source of inhibitory peptides (prey), this group isolated a 33-mer peptide (I33) that bound tightly to the enzyme. I33 inhibited both in vitro integrase activities, i.e. 3' end processing and strand transfer. Further analysis led to the selection of a shorter peptide, EBR28, corresponding to the N-terminal region of I33. Truncated variants showed that EBR28 interacted with the catalytic domain of integrase interfering with the binding of the DNA substrate. Alanine single substitution of each EBR28 residue (alanine scanning) allowed the identification of essential amino acids involved in the inhibition. The EBR28 NMR structure shows that this peptide adopts an alpha-helical conformation with amphipathic properties. Additionally, EBR28 showed a significant antiviral effect when assayed on HIV-1 infected human cells. Thus, this potentially important short lead peptide may not only be helpful to design new anti-HIV agents, but also could prove very useful in further studies of the structural and functional characteristics of HIV-1 integrase.

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