Immunoglobulin superfamily proteins: structure, mechanisms, and drug discovery

We review the recent progress made in our laboratories in structure-based drug design targeting proteins of the immunoglobulin superfamily (IgSF). We will focus on the CD4 protein, which is involved in T cell function, as a specific example of how the general concept and methodologies can be applied. Recent studies of CD4 structure and function have revealed new insight into possible mechanisms for CD4 self-association and its role in binding to major histocompatibility complex (MHC) class 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 II, and T cell receptor (TCR). Such a basic understanding of CD4 structure and mechanisms has aided the development of a new generation of potential immunotherapeutics targeting specific CD4 surface functional sites. The design and discovery of small molecular inhibitors of CD4 and other IgSF proteins, in peptide, peptidomimetic, and nonpeptidic organic forms have opened new avenues for chemical research in which peptide, organic, and more recently combinatorial chemistry techniques can be used to further develop these promising lead analogs into a new generation of effective pharmaceuticals.