Computer-assisted rational design of immunosuppressive compounds.
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.
Centre de Biochimie Structurale, UMR CNRS 9955, INSERM U414, Faculté de Pharmacie, Montpellier, France.
G
G
Grassy
B
B
Calas
A
A
Yasri
R
R
Lahana
J
J
Woo
S
S
Iyer
M
M
Kaczorek
R
R
Floc'h
R
R
Buelow
D000818:Animals; D003198:Computer Simulation; D017076:Computer-Aided Design; D016384:Consensus Sequence; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D015395:Histocompatibility Antigens Class I; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011487:Protein Conformation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D008024:Ligands; D019151:Peptide Library; D010455:Peptides