Rational design of cytotoxic T-cell inhibitors.
This study describes the use of the CD8/major histocompatibility complex (MHC) class I crystal structure as a template for the de novo design of low-molecular-weight surface mimetics. The analogs were designed from a local surface region on the CD8 alpha-chain directly adjacent to the bound MHC class I, to block the protein associations in the T-cell activation cluster that occur upon stimulation of the cytotoxic T lymphocytes (CTLs). One small conformationally restrained peptide showed dose-dependent inhibition of a primary allogeneic CTL assay while having no effect on the CD4-dependent mixed lymphocyte reaction (MLR). The analog's activity could be modulated through subtle changes in its side chain composition. Administration of the analog prevented CD8-dependent clearance of a murine retrovirus in BALB/c mice. In C57BL/6 mice challenged with the same retrovirus, the analog selectively inhibited the antiviral CTL responses without affecting the ability of the CTLs to generate robust allogeneic responses.
Tretiakova
A P
AP
Department of Pathology and Laboratory Medicine, Cancer Center, School of Medicine, MCP Hahnemann University, Philadelphia, PA 19102, USA.
Little
C S
CS
Blank
K J
KJ
Jameson
B A
BA
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D016827:CD8 Antigens / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005805:Genes, MHC Class I / Q000187:drug effects; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013154:Spleen / Q000166:cytology; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*
D000596:Amino Acids; D016827:CD8 Antigens