T-20: a model for novel anti-HIV drugs in development

In September of 1993, Drs Wild, Greenwell, and Matthews of Duke University published a letter in an AIDS research journal describing a synthetic peptide directed against the gp41 transmembrane portion of the HIV envelope, which appeared to have remarkable antiviral activity in vitro.

This 36-amino acid peptide, corresponding to residues 643 to 678 of the HIV-1LAI isolate, was originally designated DP-178. It later became known as T-20. Renamed enfuvirtide (Fuzeon) by its clinical developers at Trimeris and Roche, it belongs to a new family of antiretroviral drugs that inhibit HIV entry.

As noted in the original publication, the 50% inhibitory concentration of T-20 for HIV-1-mediated cell fusion, assessed by syncytia formation, was 0.4 nmol/L (1.7 ng/mL). This is very low, and unprecedented for a peptide. The area of gp41 against which it was directed shows limited genetic variability, and this variance did not appear to affect function. Specificity was illustrated by the fact that three-fold higher log concentrations of T-20 were required to block HIV-2 entry into target cells.

The conclusion of that original brief study was that T-20 “could serve as a lead compound in the discovery of both peptide- and nonpeptide-based drug candidates.” That turned out to be an understatement.