Structure of HIV-1 protease with KNI-272: A transition state mimetic inhibitor containing allophenylnorstatine

Inhibitors of human immunodeficiency virus type 1 protease (HIV PR) are the subject of wide interest for the development of therapeutic drugs against AIDS [1–4]. The crystal structures of numerous HIV PR/inhibitor complexes have been solved to aid the process of inhibitor design and to rationalize the structure-activity relationships (SAR) for various classes of inhibitors [5–7]. Incorporation of allophenylnorstatine (APNS) [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] into peptidomimetics can lead to highly potent inhibitors of HIV PR [8]. However, no structure of APNS containing inhibitor complexes has been reported. Recently, KNI-272, a conformationally-constrained inhibitor containing APNS (Figure la), has been shown to possess good anti-HIV activity [9]. As a step towards understanding the high affinity of this novel class of inhibitors, we determined the three dimensional structure of KNI-272 bound to HIV PR.