IMMUNOGLOBULIN SUPERFAMILY PROTEINS - STRUCTURE, MECHANISMS, AND DRUGDISCOVERY

We review the recent progress made in our laboratories in structure-ba sed drug design targeting proteins of the immunoglobulin superfamily ( IgSF). We will focus on the CD4 protein, which is involved in T cell f unction, as a specific example of how the general concept and methodol ogies can be applied. Recent studies of CD4 structure and function hav e revealed new insight into possible mechanisms for CD4 self-associati on and its role in binding to major histocompatibility complex (MHC) c lass II molecules and initiation of T cell activation. This has led to the formulation of a hypothetical model of co-oligomerization of CD4, MHC class has led to the formulation of a hypothetical model of co-ol igomerization of CD4, MHC class II, and T cell receptor (TCR). Such a basic understanding of CD4 structure and mechanisms has aided the deve lopment of a new generation of potential immunotherapeutics targeting specific CD4 surface functional sites. The design and discovery of sma ll molecular inhibitors of CD4 and other IgSF proteins, in peptide, pe ptidomimetic, and nonpeptidic organic forms have opened new avenues fo r chemical research in which peptide, organic, and more recently combi natorial chemistry techniques can be used to further develop these pro mising lead analogs into a new generation of effective pharmaceuticals . (C) 1998 John Wiley & Sons, Inc.