Lessons learned fighting HIV can be applied to anti-cancer drug design.

Introduction of a number of HIV-1 protease (PR) inhibitors as anti-AIDS drugs has drastically changed the clinical prognosis for the outcome of this disease, from almost invariably lethal to chronic. This achievement also represented the first major success of structure-based drug design, encouraging the use of similar approaches to other major diseases, such as cancer. We have now identified adult T-cell leukemia (ATL) as a possible target for a similar treatment. It is now accepted beyond a doubt that a number of cancers are caused by viruses, and by retroviruses in particular. It had been shown already 25 years ago that human T-cell leukemia virus type 1 (HTLV-1) is epidemiologically associated with ATL 1 and the current estimate is that up to 30 million people worldwide are infected with HTLV-1. Such infections are particularly prevalent in Japan, 2 and for the fraction of infected individuals who actually develop ATL, no efficacious treatment is available. 3 We postulate that designing inhibitors for HTLV-1 PR may represent a new way of preventing and/or treating ATL. HTLV-1 is a retrovirus that is in many respects similar to HIV-1. In particular, both viruses encode a protease necessary for their maturation. Although the enzymatic properties of HTLV-1 PR have been already studied in some detail, 4 no three-dimensional structure of this enzyme was available until now. The dearth of structural information hindered the design of inhibitors using the principles of rational drug design, so elegantly and successfully applied in the case of HIV-1 PR. 5 Moreover, the existing anti-HIV-1 PR inhibitors turned out to be ineffective against HTLV-1 PR. This is not surprising in view of the low (27%) sequence identity and of the documented different substrate specificities of the two enzymes. These observations punctuate the notion that accurate targets are required for successful design of drugs. Their structures need to be defined experimentally at the atomic level by either crystallography or NMR. With this objective in mind, we have recently solved the crystal structure of HTLV-1 PR 6 in complex with a specific inhibitor which mimicks an efficiently processed substrate of this enzyme. As expected, the overall fold of HTLV-1 PR is similar to that found in other retroviral proteases, including HIV-1 PR. Specifically, the enzyme is a pseudosym-metric homodimer composed of two identical subunits, which interlace their termini in a β-sheet interface supporting the active site formed by two aspartate residues. Two extended …