12704
J. Am. Chem. Soc. 1998, 120, 12704-12705
Scheme 1
Design, Synthesis, and Evaluation of a
Pyrrolinone-Peptide Hybrid Ligand for the Class II
MHC Protein HLA-DR1
Amos B. Smith, III,* Andrew B. Benowitz, Mark C. Guzman,
Paul A. Sprengeler, and Ralph Hirschmann*
Department of Chemistry, UniVersity of PennsylVania
Philadelphia, PennsylVania 19104
Edwin J. Schweiger, David R. Bolin, Zoltan Nagy,
Robert M. Campbell, Donald C. Cox, and Gary L. Olson*,†
Department of Inflammation/Autoimmune Diseases
Hoffmann-La Roche Inc., Nutley, New Jersey 07110
ReceiVed August 19, 1998
In 1992, we reported the design and synthesis of nonpeptide
â-strand peptidomimetics based on the 3,5,5-pyrrolin-4-one
scaffold.1a These polypyrrolinones, which are stable to proteases,
adopt extended conformations both in solution and in the solid
state that mimic the antiperiplanar disposition of the carbonyls
and side chains of peptidal â-strands. More recently, we success-
fully exploited the pyrrolinone scaffold to construct potent,
bioavailable, small-molecule inhibitors of the HIV-1 protease.1b-d
In this communication, we disclose the design and synthesis of a
pyrrolinone-based peptide hybrid which proved to be a competent
ligand for the rheumatoid arthritis-associated class II major
histocompatibility complex protein HLA-DR1, thereby further
demonstrating the utility of the pyrrolinone scaffold.
The primary role of the class II major histocompatibility
complex (MHC), an extracellular polymorphic2 membrane-bound
protein widely dispersed on B lymphocytes, macrophages, and
other specialized antigen-presenting cells,3 is to present antigenic
peptides4 derived from extracellular pathogens and toxins for
† Current address: Provid Research, 10 Knightsbridge Road, Piscataway,
NJ 08854.
(1) (a) Smith, A. B., III; Keenan, T. P.; Holcomb, R. C.; Sprengeler, P.
A.; Guzman, M. C.; Wood, J. L.; Carroll, P. J.; Hirschmann, R. J. Am. Chem.
Soc. 1992, 114, 10672. (b) Smith, A. B., III; Hirschmann, R.; Pasternak, A.;
Akaishi, R.; Guzman, M. C.; Jones, D. R.; Keenan, T. P.; Sprengeler, P. A.;
Darke, P. L.; Emini, E. A.; Holloway, M. K.; Schleif, W. A. J. Med. Chem.
1994, 37, 215. (c) Smith, A. B., III; Hirschmann, R.; Pasternak, A.; Guzman,
M. C.; Yokoyama, A.; Sprengeler, P. A.; Darke, P. L.; Emini, E. A.; Schleif,
W. A. J. Am. Chem. Soc. 1995, 117, 11113. (d) Smith, A. B., III; Hirschmann,
R.; Pasternak, A.; Yao, W.; Sprengeler, P. A.; Holloway, M. K.; Kuo, L. C.;
Chen, Z.; Darke, P. L.; Schleif, W. A. J. Med. Chem. 1997, 40, 2440 and
references therein.
(2) Kappes, D.; Strominger, J. L. A. ReV. Biochem. 1988, 57, 991.
(3) (a) Unanue, E. R.; Allen, P. M. Science 1987, 236, 551. (b) Steinman,
R. M. Annu. ReV. Immunol. 1991, 9, 271.
(4) (a) Adorini, L.; Muller, S.; Cardinaux, F.; Lehmann, P. V.; Falcioni,
F.; Nagy, Z. A. Nature 1988, 334, 623. (b) Rudensky, A. Y.; Preston-Hurlburt,
P.; Hong, S.-C.; Barlow, A.; Janeway, C. A., Jr. Nature 1991, 353, 622. (c)
Hunt, D. F.; Hanspeter, M.; Dickinson, T. A.; Shabanowitz, J.; Cox, A. L.;
Sakaguchi, K.; Appella, E.; Grey, H. M.; Sette, A. Science 1992, 256, 1817.
(d) Chicz, R. M.; Urban, R. G. Immunol. Today 1994, 15, 155. (e) Engelhard,
V. H. Annu. ReV. Immunol. 1994, 12, 181.
(5) Todd, J. A.; Acha-Orbea, H.; Bell, J. I.; Chao, N.; Fronek, Z.; Jacob,
C. O.; McDermott, M.; Sinha, A. A.; Timmerman, L.; Steinman, L.; McDevitt,
H. O. Science 1988, 240, 1003.
(6) (a) Brown, J. H.; Jardetzky, T. S.; Gorga, J. C.; Stern, L. J.; Urban, R.
G.; Strominger, J. L.; Wiley, D. C. Nature 1993, 364, 33. (b) 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. (c) Jardetzky, T. Structure 1997, 5, 159.
(7) Hammer, J.; Valsasnini, P.; Tolba, K.; Bolin, D.; Higelin, J.; Takacs,
B.; Sinigaglia, F. Cell 1993, 74, 197.
(8) (a) Hammer, J.; Belunis, C.; Bolin, D.; Papadopoulos, J.; Walsky, R.;
Higelin, J.; Danho, W.; Sinigaglia, F.; Nagy, Z. Proc. Natl. Acad. Sci. U.S.A.
1994, 91, 4456. (b) Bolin, D.; Campbell, R. Hoffmann-La Roche Inc.,
unpublished results.
(9) The structure assigned to each new compound is in accord with its
infrared, 500-MHz 1H NMR, and 125-MHz 13C NMR spectra, as well as
appropriate parent ion identification by high-resolution mass spectrometry.
(10) (a) Karady, S.; Amato, J. S.; Weinstock, L. M. Tetrahedron Lett. 1984,
25, 4337. (b) Seebach, D.; Fadel, A. HelV. Chim. Acta 1985, 68, 1243. (c)
Seebach, D.; Aebi, J. D.; Gander-Coquoz, M.; Naef, R. HelV. Chim. Acta
1987, 70, 1194.
inspection by CD4 T cells of the immune system. Inhibition of
this process holds considerable promise for the treatment of
numerous autoimmune diseases.5
The recent X-ray crystal analysis by Wiley and co-workers6a,b
revealed that the HLA-DR1 MHC class II protein binds the
influenza virus hemagglutinin peptide fragment PKYVKQN-
TLKLAT (HA 306-318)6b in an extended, â-strand-like confor-
mation. The presence of anchor residues at positions 1 and 9
(Scheme 1) in conjunction with a complex network of hydrogen
bond interactions between the HA 306-318 backbone and the
amino acid side chains in the DR1 MHC binding site are
postulated to account for a large portion of the binding energy.4,7
On the basis of alanine scans of HA 306-318 and related 7-mer
peptide ligands,8 we postulated that the side chains of the VKQN
sequence in HA 306-318 could be altered without significantly
affecting HLA-DR1 binding. Indeed, control peptide PKYGLLL-
TLKLAT bound to the HLA-DR1 protein with an IC50 of 176
nM, comparable to an IC50 of 89 nM for the native HA 306-318
peptide. On the basis of this information, we speculated that
bispyrrolinone 2a (Scheme 1) might serve as a viable replacement
for the amide backbone of the VKQN sequence of HA 306-318.
Molecular modeling revealed that the global low-energy confor-
mations of the bispyrrolinone segment of 1 and the corresponding
region of HA 306-318 bound to HLA-DR1 would be quite similar.
Moreover, with the exception of a hydrogen bond between Gln-9
of HLA-DR1 and the N-H at position 4 of HA 306-318, the
hydrogen bonding network was predicted to remain intact. Integral
to this design was the expectation that Fmoc derivative 2b would
permit use of Fmoc-based solid-phase peptide synthesis to
construct the hybrid ligand 1.
10.1021/ja982973t CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/20/1998