CONTEXT

The majority of the chemotherapeutic agents used in AIDS treatments target the polymerase activity of HIV-1 reverse transcriptase, such as nucleoside reverse transcriptase inhibitors (NRTIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs).

In order to propose new classes of HIV inhibitors, extensive efforts have been made in the design of molecules that target protein/protein interfaces required for viral entry, replication and maturation.

The thumb domain plays an important role in the catalysis and integrity of the dimeric form of reverse transcriptase, thereby constituting a potential target for the design of novel antiviral compounds [Morris et al. (1999) Biochemistry 38, 15097-15103].

A previous peptide designed as an inhibitor of reverse transcriptase by interfering with the conformational change associated with full activation of the enzyme significantly blocked reverse transcriptase maturation in vitro, but lacked antiviral activity [Morris et al. (1999) J. Biol. Chem. 274(35), 24941-24946].

Therefore, the inventors have designed a new series of polypeptides derived from the thumb subdomain of HIV-1 reverse transcriptase.

Further references:

Depollier et al. (2005) Biochemistry 44, 1909-1918

Agopian et al. (2007) J. Mol. Biol. 373, 127-140

Agopian et al. (2009) J. Biol. Chem. 284(1), 254-264