Design and Synthesis of a Competent Pyrrolinone−Peptide Hybrid Ligand for the Class II Major Histocompatibility Complex Protein HLA-DR1

Smith, Amos B.; Benowitz, Andrew B.; Sprengeler, Paul A.; Barbosa, Joseph; Guzman, Mark C.; Hirschmann, Ralph; Schweiger, E. J.; Bolin, David; Nagy, Zoltán Á.; Campbell, Robert M.; Çox, Donald C.; Olson, Gary L.

doi:10.1021/ja991251e

Cited by 44 publications

(48 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This scaffold was also useful for the construction of pyrrolinone-peptide hybrids as ligand for the class II major histocompatibility complex (MHC) protein HLA-DR1 [142]; on the basis of the X-rays structure of the HA 306-318 peptide bound to the MHC protein HLA-DR1, the bispyrrolinone has been introduced as a viable replacement for the tetrapeptidic sequence VKQN (residues 309-312) of HA 306-318, mimicking the peptidal β-strand.…”

Section: F) Pyrrolinonesmentioning

confidence: 99%

Privileged Structures as Leads in Medicinal Chemistry

Costantino¹,

Barlocco

2006

CMC

316

View full text Add to dashboard Cite

The sol-gel process is an inorganic polymerization process taking place in mild conditions, allowing the association of mineral phases with organic or biological systems. The possibility to immobilize drugs, enzymes, antibodies and even whole cells without loss of their biological activity led to the development of diagnostic tools, drug delivery carriers as well as new hosts for artificial organ design. These systems take profit from the wide variety of chemical compositions, dimensions and forms that can be achieved via sol-gel chemistry. Recent advances involve multi-functional "smart" devices combining biocompatibility, biological activity and stimuli-responsive materials. The design of such novel devices with significant added value when compared to current products is probably a key factor when foreseeing industrial developments of sol-gel materials in medicinal science.

show abstract

Section: F) Pyrrolinonesmentioning

confidence: 99%

Privileged Structures as Leads in Medicinal Chemistry

Costantino¹,

Barlocco

2006

CMC

316

View full text Add to dashboard Cite

show abstract

“…Equally exciting, the X-ray structure of co-crystallized 50 and HLA-DR1 obtained by the Wiley group34b mimicked closely the polyproline type II conformation of peptide HA-306-318, a result that demonstrates that the pyrrolinone scaffold can serve as a direct replacement of an amino acid sequence in a bioactive peptide, involving an extended conformation.…”

Section: Major Histocompatibility Complex Hybrid Ligands and Matrix Mmentioning

confidence: 77%

“…In 1994 the late Don Wiley and colleagues, established that class II MHC molecules bind antigenic peptides in an extended, polyproline type II conformation 33. In collaboration with Olsen at Hoffmann La Roche, we initiated a program to design a pyrrolinone-peptide hybrid ligand for HLA-DR1 34. The design was based on an analog of the potent peptide HA 306-318 (Figure 10).…”

Section: Major Histocompatibility Complex Hybrid Ligands and Matrix Mmentioning

confidence: 99%

“…Affinity-binding experiments revealed that the pyrrolinone-peptide hybrid ( 50 ) was a competent ligand for HLA-DR1 (IC 50 137 nM), compared both to HA 306-318 (89 nM) and the control peptide 49 (176 nM) 34. Equally exciting, the X-ray structure of co-crystallized 50 and HLA-DR1 obtained by the Wiley group34b mimicked closely the polyproline type II conformation of peptide HA-306-318, a result that demonstrates that the pyrrolinone scaffold can serve as a direct replacement of an amino acid sequence in a bioactive peptide, involving an extended conformation.…”

Section: Major Histocompatibility Complex Hybrid Ligands and Matrix Mmentioning

confidence: 99%

See 1 more Smart Citation

Pyrrolinone-Based Peptidomimetics.“Let the Enzyme or Receptor be the Judge”

2010

Self Cite

View full text Add to dashboard Cite

Peptides and proteins, evolved by nature to perform vital biological functions, would constitute ideal candidates for therapeutic intervention were it not for their generally poor pharmacokinetic profiles. Nonpeptide peptidomimetics have thus been pursued because they might overcome these limitations while maintaining both the potency and selectivity of the parent peptide or protein. Since the late 1980s, we have sought to design, synthesize, and evaluate a novel, proteolytically stable nonpeptide peptidomimetic scaffold consisting of a repeating structural unit amenable to iterative construction; a primary concern is maintaining both the appropriate peptide-like side-chains and requisite hydrogen bonding. In this Account, we detail how efforts in the Smith–Hirschmann laboratories culminated in the identification of the 3,5-linked polypyrrolinone scaffold. We developed effective synthetic protocols, both in solution and on solid supports, for iterative construction of diverse polypyrrolinones that present functionalized peptide-like side-chains. As a result of the rigid nature of the pyrrolinone scaffold, control over the backbone conformation could be exerted by modulation of the stereogenicity of the constituent monomers and the network of intramolecular hydrogen bonding. The extended conformation of the homochiral 3,5-linked polypyrrolinone scaffold proved to be an excellent mimic for β-strands and β-sheets. Application to enzyme inhibitor design and synthesis led not only to modest inhibitors of the aspartic acid protease renin and the matrix metalloprotease class of enzymes, but importantly to bioavailable HIV-1 protease inhibitors with subnanomolar binding constants. The design and synthesis of a competent peptide–pyrrolinone hybrid ligand for the class II major histocompatibility complex (MHC) antigen protein HLA-DR1 further demonstrated the utility of the 3,5-polypyrrolinone motif as a mimic for the extended polyproline type II peptide backbone. Equally important, we sought to define, by synthesis, the additional conformational space accessible to the polypyrrolinone structural motif, with the ultimate goal of accessing pyrrolinone-based turn and helix mimetics. Towards this end, a mono-N-methylated bispyrrolinone was found to adopt an extended helical array in the solid state. Subsequent synthesis of d,l-alternating (heterochiral) tetrapyrrolinones both validated the expected turn conformations in solution and led to a functionally active mimetic of a peptidal β-turn (similar to somatostatin). Finally, the design, synthesis, and structural evaluation of both acyclic and cyclic heterochiral (that is, d,l-alternating) hexapyrrolinones yielded nanotube-like assemblies in the solid state. Taken together, these results illustrate the remarkable potential of the 3,5-linked polypyrrolinone scaffold as β-strand, β-sheet, β-turn, and potentially helical peptidomimetics.

show abstract

“…Smith and co-workers substituted a peptidomimetic pyrolinone for a four amino-acid segment in the known thirteen amino acid peptide ligand (virus hemagglutinin (HA) peptide) and reported favorable binding (IC 50 = 137 nM in comparison to IC 50 = 89 nM for the native ligand). Further attempts to modify the four residue substitution based on molecular modeling results yielded poorer affinity ligands (IC 50 > 100 lM) [76,77]. Woulfe, et al reported a seven amino acid long peptidomimetic inhibitor that competes favorably with the HA peptide (IC 50 = 50 nM compared to IC 50 = 62 nM for HA as reported in their work) [78].…”

Section: Introductionmentioning

confidence: 98%

Ligand design by a combinatorial approach based on modeling and experiment: application to HLA-DR4

Evensen

Joseph‐McCarthy

Weiss

et al. 2007

J Comput Aided Mol Des

View full text Add to dashboard Cite

Combinatorial synthesis and large scale screening methods are being used increasingly in drug discovery, particularly for finding novel lead compounds. Although these ''random'' methods sample larger areas of chemical space than traditional synthetic approaches, only a relatively small percentage of all possible compounds are practically accessible. It is therefore helpful to select regions of chemical space that have greater likelihood of yielding useful leads. When three-dimensional structural data are available for the target molecule this can be achieved by applying structure-based computational design methods to focus the combinatorial library. This is advantageous over the standard usage of computational methods to design a small number of specific novel ligands, because here computation is employed as part of the combinatorial design process and so is required only to determine a propensity for binding of certain chemical moieties in regions of the target molecule. This paper describes the application of the Multiple Copy Simultaneous Search (MCSS) method, an active site mapping and de novo structure-based design tool, to design a focused combinatorial library for the class II MHC protein HLA-DR4. Methods for the synthesizing and screening the computationally designed library are presented; evidence is provided to show that binding was achieved. Although the structure of the protein-ligand complex could not be determined, experimental results including cross-exclusion of a known HLA-DR4 peptide ligand (HA) by a compound from the library. Computational model building suggest that at least one of the ligands designed and identified by the methods described binds in a mode similar to that of native peptides.

show abstract

Design and Synthesis of a Competent Pyrrolinone−Peptide Hybrid Ligand for the Class II Major Histocompatibility Complex Protein HLA-DR1

Cited by 44 publications

References 63 publications

Privileged Structures as Leads in Medicinal Chemistry

Privileged Structures as Leads in Medicinal Chemistry

Pyrrolinone-Based Peptidomimetics.“Let the Enzyme or Receptor be the Judge”

Ligand design by a combinatorial approach based on modeling and experiment: application to HLA-DR4

Contact Info

Product

Resources

About