Nature Biotechnology
16, 748 - 752 (1998)
doi:10.1038/nbt0898-748
Computer-assisted rational design of immunosuppressive compoundsGérard Grassy1, 5, Bernard Calas2, 5, Abdelaziz Yasri3, Roger Lahana3, *, Jacky Woo4, Suhasini Iyer4, Michel Kaczorek3, Robert Floc'h4
& Roland Buelow4
1Centre de Biochimie Structural. UMR CNRS 9955, INSERM U414, Faculté de Pharmacie, 15 Av. Charles Flahault, 34060 Montpellier, France.
2CRBM, UPR 9008 CNRS, 34000 Montpellier, France.
3Synt:em, Parc Scientifique Georges Besse, 30000 Nîmes, France.
4SangStat Medical Corporation, Menlo Park, CA.
5These authors contributed equally to this work.
*(e-mail: rlahana@syntem.eerie.fr). We describe the rational design of immunosuppressive peptides without relying on information regarding their receptors or mechanisms of action. The design strategy uses a variety of topological and shape descriptors in combination with an analysis of molecular dynamics trajectories for the identification of potential drug candidates. This strategy was applied to the development of immunosuppressive peptides with enhanced potency. The lead compounds were peptides, derived from the heavy chain of HLA class I, that modulate immune responses in vitro and in vivo. In particular, a peptide derived from HLA-B2702, amino acids 75−84 (2702.75−84) prolonged skin and heart allograft survival in mice. The biological activity of the rationally designed peptides was tested in a heterotopic mouse heart allograft model. The molecule predicted to be most potent displayed an immunosuppressive activity approximately 100 times higher than the lead compound.
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