Design, synthesis, and crystal structure of a pyrrolinone-based peptidomimetic possessing the conformation of a .beta.-strand: potential application to the design of novel inhibitors of proteolytic enzymes

Smith, Amos B.; Keenan, Terence P.; Holcomb, Ryan C.; Sprengeler, Paul A.; Guzman, Mark C.; Wood, John L.; Carroll, Patrick J.; Hirschmann, Ralph

doi:10.1021/ja00052a093

Cited by 143 publications

(66 citation statements)

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“…Gellman and his colleagues [156,157] suggested that heterochiral dinipecotic acid segments, R-Nip-S-Nip and S-Nip-R-Nip, could also promote reverse-turn formation. Smith et al also established the 3,5- [158,159] (nitrogen displaced) and 2,5-linked [160] (carbonyl displaced) homochiral polypyrrolinone motif as excellent b-sheet/b-strand mimetics both in the solid state and in solution, and further demonstrated that 3,5-linked heterochiral polypyrrolinones preferentially adopt a turn conformation [161]. Che and Marshall [162] suggested a combined approach -CTPs based on heterochiral dipeptides of chimeric amino acids -to be used as novel conformational templates (Figure 13), for instance, cyclo-(D-Pro-L-Pro-D-Pro), as synthetic routes to chimeric prolines containing 2-, 3-, 4-, or 5-substituents are abundant.…”

Section: Ctp Scaffoldsmentioning

confidence: 94%

Development of small molecules designed to modulate protein–protein interactions

Che

Brooks

Marshall

2006

J Comput Aided Mol Des

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Protein-protein interactions are ubiquitous, essential to almost all known biological processes, and offer attractive opportunities for therapeutic intervention. Developing small molecules that modulate protein-protein interactions is challenging, owing to the large size of protein-complex interface, the lack of well-defined binding pockets, etc. We describe a general approach based on the "privileged-structure hypothesis" [Che, Ph.D. Thesis, Washington University, 2003] - that any organic templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as protein-complex antagonists--to address the challenges inherent in the discovery of small-molecule inhibitors of protein-protein interactions.

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Section: Ctp Scaffoldsmentioning

confidence: 94%

Development of small molecules designed to modulate protein–protein interactions

Che

Brooks

Marshall

2006

J Comput Aided Mol Des

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“…The MTA is proposed for flexible peptides such as NT(8-13), whose receptor-bound conformation is unknown. In contrast, the scaffolding approach can apply only to peptides of known conformation, such as the equine angiotensinogen fragment (H-Leu-Leu-Vat-Tyr-OMe) [11] and the Gly-Ala-Ala-Gly fraga~aent [8], or to relatively rigid peptides such as the cyclic hexapeptide SRIF [9].…”

Section: The Multiple Template Approachmentioning

confidence: 99%

Rational design of novel neurotensin mimetics: Discovery of a pharmacologically unprecedented agent exhibiting concentration-dependent dual effects as antagonist and full agonist

Pang¹,

Zaidi²,

Kozikowski³

et al. 1994

J Computer-Aided Mol Des

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We report the rational design of novel neurotensin mimetics through use of the Multiple Template Approach. This approach is based on our notion that a flexible peptide can be replaced by a partially flexible molecule, identified through testing a comparatively small number of molecules possessing a different intrinsic availability of conformations of the native peptide. The Multiple Template Approach has culminated in the discovery of a pharmacologically unprecedented agent, which behaves as a neurotensin antagonist at low concentration and as a full neurotensin agonist at high concentration.

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“…2 Computational studies suggested that oligomers based on this repeating vinylogous amide motif held the promise of adopting structures similar, but not identical to, the three secondary structures of peptides and proteins 2,3. As such, the polypyrrolinones constituted early examples of foldamers as defined by Gellman,4,1a,b and elegantly demonstrated for β-peptides both by Seebach5,1c and Gellman 4b,1a,b.…”

mentioning

confidence: 97%

Design, Synthesis, and Structural Analysis of d,l-Mixed Polypyrrolinones. 1. From Nonpeptide Peptidomimetics to Nanotubes

et al. 2010

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To expand the potential conformational space available to the polypyrroline structural motif, an open chain, D,L-alternating hexapyrrolinone was designed and synthesized. Structural studies, including solution NMR and X-Ray crystallographic analysis, revealed that the hexapyrrolinone adopts a turn conformation both in solution and in the solid state, with aggregation in solution and a nanotube-like quaternary structure in the crystal.A major achievement in the field of non-peptide peptidomimetics would comprise the design and synthesis of biologically relevant mimics, capable of adopting conformations similar to the three principal secondary structures accessible to peptides and proteins (e.g., β-turns, β-strands, or α-helices), with conformational control manifest simply via structural modification of the side-chains and/or the stereogenicity of the constituent monomers. To date, only a limited number of conformationally versatile nonpeptide peptidomimetics have been reported.1In 1992, the Hirschmann-Smith collaboration reported the design and synthesis of a new class of peptidomimetics based on the pyrrolinone scaffold ( Figure 1).2 Computational studies suggested that oligomers based on this repeating vinylogous amide motif held the promise of adopting structures similar, but not identical to, the three secondary structures of peptides and proteins.2 , 3 As such, the polypyrrolinones constituted early examples of foldamers as defined by Gellman,4 , 1a,b and elegantly demonstrated for β-peptides both by Seebach5 , 1c and Gellman.4b , 1a,b Pleasingly, initial studies demonstrated that homochiral polypyrrolinones (e.g., all D),6 such as (−)-1, can adopt extended parallel (1a , Figure 1) or antiparallel (1b) β-strand/sheet mimics, depending on the presence or absence of a Boc Cterminus.2 , 3 , 7 This observation led to the design and synthesis of a series of potent pyrrolinone-based enzyme inhibitors,8 requiring the β-strand/-sheet motif, including metalloproteases,9 and orally bioavailable HIV-1 protease inhibitors,10 as well as a peptidepyrrolinone hybrid ligand for the class II MHC protein HLA-DR1.11

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Design, synthesis, and crystal structure of a pyrrolinone-based peptidomimetic possessing the conformation of a .beta.-strand: potential application to the design of novel inhibitors of proteolytic enzymes

Cited by 143 publications

References 0 publications

Development of small molecules designed to modulate protein–protein interactions

Development of small molecules designed to modulate protein–protein interactions

Rational design of novel neurotensin mimetics: Discovery of a pharmacologically unprecedented agent exhibiting concentration-dependent dual effects as antagonist and full agonist

Design, Synthesis, and Structural Analysis of d,l-Mixed Polypyrrolinones. 1. From Nonpeptide Peptidomimetics to Nanotubes

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