Peptide Sci. 1997, in press
Kimmel Cancer Institute, Jefferson Medical College,
Thomas Jefferson University, Philadelphia, Pennsylvania 19107
Abstract: 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 and CD8 proteins, both of which are involved in T cell function, as specific examples of how the general concept and methodologies can be applied. Recent studies of CD4 protein surface epitopes critical for its binding to histocompatibility complex (MHC) class II molecules and for initiation of T cell activation have led to the development of a new generation of potential immunotherapeutics. In this review, we also discussed the possible models for CD4 oligomerization and complex formation with MHC class II based on dual dimerization sites located at its first and fourth domains. These models provided a structural basis for the biological activity observed recently for peptide and organic inhibitors of CD4 function and revealed new targets for rational drug design. The design and discovery of small molecular inhibitors of IgSF function, in peptide, peptidomimetic, and non-peptidic organic forms, have opened new avenues for medicinal chemistry research in which synthetic chemistry techniques can be used to further develop these promising lead analogs into a new generation of effective pharmaceuticals.
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