Tetrapeptide derived inhibitors of complexation of a class II MHC: Fully unnatural ligands

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 14, 1999, Pages 2115-2118

  Jones, A Brian ^a   Acton III, John J ^a   Adams, Alan D ^a   Yuen, Winston ^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; HYDROGEN BOND; LIGAND BINDING; MAJOR HISTOCOMPATIBILITY COMPLEX; PROTEIN BINDING; PROTEIN MODIFICATION; PROTEIN STRUCTURE;

DRUG DESIGN; HISTOCOMPATIBILITY ANTIGENS CLASS II; INHIBITORY CONCENTRATION 50; LACTAMS; LIGANDS; MOLECULAR MIMICRY; PEPTIDES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0033584209     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00334-0     Document Type: Article

References (9)

1. Jones, A. B.; Acton, J. J.; Rivetna, M. N.; Cummings, R. T.; Nichols, E. A.; Schwartz, C. D.; Wicker, L. S.; Hermes, J. D. Bioorg. Med. Chem. Lett. 1998, preceding report.
2. Humphrey, M. J.; Ringrose, P. S. Drug Metab.Rev. 1986, 17, 283.
3. A full accounting of intra-endosomal proteases is not available. Members of the cathepsin family have been implicated in antigen processing but are clearly not the only players (e.g., Deussing, J.; Roth, W.; Saftig P.; Ploegh, H. L.; Villadangos, J. A. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 4516). It is reasonable to assume that almost any unguarded peptide bond would provide a weak link in a putative inhibitor.
4. 50 for simplicity.
5. Acton, J. J.; Jones, A. B. Tetrahedron Lett. 1996, 37, 4319.
6. A formal assessment of the value of such lactams in conferring proteolytic stability appears lacking. However such a study may be redundant as this property is likely to vary from case to case. One cannot assume improved stability, even where improved in vivo properties are observed. However it seems unlikely that such a modification would increase susceptibility.
7. Dutta, A. S.; Giles, M. B. J. Chem. Soc. Perkin 1, 1976, 244
8. Janda, K. D.; Han, H. J. Am. Chem. Soc. 1996, 118, 2539 and references therein.
9. There is evidence for discrete steps during the peptide binding/displacement process that may involve class II conformational changes (Sadegh-Nasserl, S.; Stern, L. J.; Wiley, D. C.; Germain, R. N. Nature 1994, 370, 647, and references therein).