Tetrapeptide derived inhibitors of complexation of a class II MHC: The peptide backbone is not inviolate

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 14, 1999, Pages 2109-2114

  Jones, A Brian ^a   Acton III, John J ^a   Rivetna, Meheryar N ^a   Cummings, Richard T ^a   Cubbon, Rose M ^a   Nichols, Elizabeth A ^a   Schwartz, Cheryl D ^a   Wicker, Linda S ^a   Hermes, Jeffrey D ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2;

ARTICLE; COMPLEX FORMATION; IMMUNE RESPONSE; MAJOR HISTOCOMPATIBILITY COMPLEX; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE;

BINDING SITES; HEMAGGLUTININS; HISTOCOMPATIBILITY ANTIGENS CLASS II; HLA-DR1 ANTIGEN; INHIBITORY CONCENTRATION 50; LACTAMS; LIGANDS; MOLECULAR MIMICRY; MOLECULAR STRUCTURE; PEPTIDES; PHOSPHOPROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSCRIPTION FACTORS;

EID: 0033584148     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00333-9     Document Type: Article

References (25)

1. e-mail; brian_jones@merck.com
2. For a convenient introduction and lead references see Mellman, I.; Pierre, P.; Amigorena, S. Curr. Opinion Cell Biol. 1995, 7, 564.
3. See for example Wucherpfennig, K. W.; Strominger, J. L. J. Exp. Med. 1995, 181, 1596.
4. See for example Gao, X.; Olsen, N. J.; Pincus, T.; Stastny, P. Arthritis Rheum. 1990, 33, 939.
5. Guery, J-C; Adorini, L. Crit. Rev. Immunol. 1993, 13, 195.
6. Cummings, R. presented at McMaster University, May 1996.
7. Cunningham, B. R; Rivetna, M.; Tolman, R. L.; Flattery, S. J.; Nichols, E. A.; Schwartz, C.D.; Wicker, L. S.; Hermes, J. D.; Jones, A. B. Bioorg. Med. Chem. Lett. 1997, 7, 19.
8. Wilkinson, A.J. Chem. & Biol. 1996, 3, 519.
9. Stern, L. J.; Brown, J. H.; Jardetzky, T. S.; Gorga, J. C.; Urban, R. G.; Strominger, J. L.; Wiley, D. C. Nature 1994, 368, 215.
10. Hill, C. M.; Liu, A.; Marshall, K. W.; Mayer, J.; Jorgensen, B.; Yuan, B.; Cubbon, R.; Nichols, E. A.; Wicker, L. S.; Rothbard, J. B. J. Immunol. 1994, 152, 2890.
11. 7), substantially peptidic ligands (e.g., Smith, A. B.; Benowitz, A. B.; Guzman, M. C.; Sprengler, P. A.; Hirschmann, R.; Schweiger, E. J.; Bolin, D. R.; Nagy, Z.; Campbell, R. M.; Cox, D. C.; Olson, G. L. J. Am. Chem. Soc. 1998, 120, 12704) or weak retro-inverso peptides (e.g., Howard, S. C.; Zacheis, M. L.; Bono, C. P.; Welply, J. K.; Hanson, G. J.; Vuletich, J. L.; Bedell, L. J.; Summers, N. L.; Schwartz, B. D.; Woulfe, S. L. Protein Pept. Lett. 1997, 4, 63).
12. 7), substantially peptidic ligands (e.g., Smith, A. B.; Benowitz, A. B.; Guzman, M. C.; Sprengler, P. A.; Hirschmann, R.; Schweiger, E. J.; Bolin, D. R.; Nagy, Z.; Campbell, R. M.; Cox, D. C.; Olson, G. L. J. Am. Chem. Soc. 1998, 120, 12704) or weak retro-inverso peptides (e.g., Howard, S. C.; Zacheis, M. L.; Bono, C. P.; Welply, J. K.; Hanson, G. J.; Vuletich, J. L.; Bedell, L. J.; Summers, N. L.; Schwartz, B. D.; Woulfe, S. L. Protein Pept. Lett. 1997, 4, 63).
13. 7), substantially peptidic ligands (e.g., Smith, A. B.; Benowitz, A. B.; Guzman, M. C.; Sprengler, P. A.; Hirschmann, R.; Schweiger, E. J.; Bolin, D. R.; Nagy, Z.; Campbell, R. M.; Cox, D. C.; Olson, G. L. J. Am. Chem. Soc. 1998, 120, 12704) or weak retro-inverso peptides (e.g., Howard, S. C.; Zacheis, M. L.; Bono, C. P.; Welply, J. K.; Hanson, G. J.; Vuletich, J. L.; Bedell, L. J.; Summers, N. L.; Schwartz, B. D.; Woulfe, S. L. Protein Pept. Lett. 1997, 4, 63).
14. There are a number of reports of the binding of modified peptides to MHC class I. The least peptidic of these retain four unaltered peptide residues and appear to be rather weak ligands (Bianco, A.; Brock, C.; Zabel, C.; Walk, T.; Walden, P.; Jung, G. J. Biol. Chem., 1998, 273, 28759).
15. Distantly related though non-MHC encoded proteins are capable of presenting non-peptides (e.g., hCD1b & lipid antigen; Sieling, P.A.; Chaterjee, D.; Porcelli, S. A.; Prigozy, T. I.; Mazzaccaro, R. J.; Soriano, T.; Bloom, B. R.; Brenner, M. B.; Kronenberg, M.; Brennan, P. J.; Modlin, R. L. Science 1995, 269, 227). The X-ray structure of mCD1d1 highlights the global structural similarity of CD1 to MHC proteins, but also clearly differentiates it in terms of ligand binding characteristics (Zeng, Z.-H.; Castano, A. R.; Segelke, B. W.; Stura, E. A.; Peterson, P. A.; Wilson, I. A. Science 1997, 277, 339).
16. Distantly related though non-MHC encoded proteins are capable of presenting non-peptides (e.g., hCD1b & lipid antigen; Sieling, P.A.; Chaterjee, D.; Porcelli, S. A.; Prigozy, T. I.; Mazzaccaro, R. J.; Soriano, T.; Bloom, B. R.; Brenner, M. B.; Kronenberg, M.; Brennan, P. J.; Modlin, R. L. Science 1995, 269, 227). The X-ray structure of mCD1d1 highlights the global structural similarity of CD1 to MHC proteins, but also clearly differentiates it in terms of ligand binding characteristics (Zeng, Z.-H.; Castano, A. R.; Segelke, B. W.; Stura, E. A.; Peterson, P. A.; Wilson, I. A. Science 1997, 277, 339).
17. Early accounts of some of our findings in this area were presented at the 25th National Medicinal Chemistry Symposium, Ann Arbor, MI, June 1996 and at the 14th International Medicinal Chemistry Symposium, Maastricht, Netherlands, September 1996.
18. 50 for simplicity.
19. 2NH) surrogate was compared in the FVNvaL series rather than the FRNvaL series of lead 1 because of chemical diffculties associated with attempting to use arginal derivatives.
20. Certain data presented herein, certain unpublished data and also Adams, A. D.; Yuen, W.; Jones, A. B.; Acton, J. A. presented at the 25th National Medicinal Chemistry Symposium, Ann Arbor, MI, June 1996.
21. 7 that the Phe⇒Cha transition generally afforded a ∼20-fold boost in potency.
22. Friedinger, R. M.; Schwenk Perlow, D.; Veber, D. F. J. Org. Chem. 1988, 31, 1369.
23. We also prepared a series of analagous δ-lactams and saw a similar feature. The δ-lactams were consistently weaker inhibitors than the corresponding γ-lactams.
24. Replacement of the P1 residue in all-L tripeptides by 3-(cyclohexyl)propanoyl or 3-(cyclohexyl)propyl was also modestly successful - Rusiecki, V.; Warne, S.; Tolman, R.; Wicker, L.; Schwartz, C.; Nichols, E.; Hermes, J. presented at 20th IUPAC Symposium on the Chemistry of Natural Products, Chicago, Sept. 1996). See also Hanson, G. J.; Vuletich, J. L.; Bedell, L. J.; Bono, C. P.; Howard, S. C.; Welply, J. K., Woulfe, S. L.; Zacheis, M. L. Bioorg. Med. Chem. Lett. 1996, 6, 1931.
25. Replacement of the P1 residue in all-L tripeptides by 3-(cyclohexyl)propanoyl or 3-(cyclohexyl)propyl was also modestly successful - Rusiecki, V.; Warne, S.; Tolman, R.; Wicker, L.; Schwartz, C.; Nichols, E.; Hermes, J. presented at 20th IUPAC Symposium on the Chemistry of Natural Products, Chicago, Sept. 1996). See also Hanson, G. J.; Vuletich, J. L.; Bedell, L. J.; Bono, C. P.; Howard, S. C.; Welply, J. K., Woulfe, S. L.; Zacheis, M. L. Bioorg. Med. Chem. Lett. 1996, 6, 1931.