Template-Constrained Cyclic Peptides: Design of High-Affinity Ligands for GPIIb/IIIa

Jackson, Sharon; DeGrado, William F.; Dwivedi, Anil Kumar; Parthasarathy, Anju; Higley, A.; Krywko, J.; Rockwell, A. L.; Markwalder, Jay A.; Wells, Gregory J.

doi:10.1021/ja00087a007

Cited by 165 publications

(109 citation statements)

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“…One excellent example has been with the tripeptide RGD sequence, in which the cyclized peptide was constrained in a rigid ␤-turn structure (21). This was accomplished by the addition of nonpeptidic constituents that mimic the structural properties of the cyclic peptide and the substitution of methyl groups for hydrogen atoms in the peptide backbones.…”

Section: Discussionmentioning

confidence: 99%

“…This was accomplished by the addition of nonpeptidic constituents that mimic the structural properties of the cyclic peptide and the substitution of methyl groups for hydrogen atoms in the peptide backbones. The result is a dramatic decrease in the rotational freedom of the peptide in solution with a corresponding increase in affinity for GPIIb/IIIa of 3 orders of magnitude (21). An additional advantage of replacing residues with a nonpeptidic substitute is an increased stability to proteolysis (21).…”

Section: Discussionmentioning

confidence: 99%

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Binding Properties of a Peptide Derived from β-Lactamase Inhibitory Protein

Rudgers¹,

Huang²,

Palzkill

2001

Antimicrob Agents Chemother

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To overcome the antibiotic resistance mechanism mediated by ␤-lactamases, small-molecule ␤-lactamase inhibitors, such as clavulanic acid, have been used. This approach, however, has applied selective pressure for mutations that result in ␤-lactamases no longer sensitive to ␤-lactamase inhibitors. On the basis of the structure of ␤-lactamase inhibitor protein (BLIP), novel peptide inhibitors of ␤-lactamase have been constructed. BLIP is a 165-amino-acid protein that is a potent inhibitor of TEM-1 ␤-lactamase (K i ‫؍‬ 0.3 nM). The cocrystal structure of TEM-1 ␤-lactamase and BLIP indicates that residues 46 to 51 of BLIP make critical interactions with the active site of TEM-1 ␤-lactamase. A peptide containing this six-residue region of BLIP was found to retain sufficient binding energy to interact with TEM-1 ␤-lactamase. Inhibition assays with the BLIP peptide reveal that, in addition to inhibiting TEM-1 ␤-lactamase, the peptide also inhibits a class A ␤-lactamase and a class C ␤-lactamase that are not inhibited by BLIP. The crystal structures of class A and C ␤-lactamases and two penicillin-binding proteins (PBPs) reveal that the enzymes have similar threedimensional structures in the vicinity of the active site. This similarity suggests that the BLIP peptide inhibitor may have a broad range of activity that can be used to develop novel small-molecule inhibitors of various classes of ␤-lactamases and PBPs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Binding Properties of a Peptide Derived from β-Lactamase Inhibitory Protein

Rudgers¹,

Huang²,

Palzkill

2001

Antimicrob Agents Chemother

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“…Smaller rigid nonpeptide molecules may also serve as linkers; an important example of this is meta-(aminomethyl)benzoic acid (Mamb) [38]. The ability of Mamb to restrict peptide conformation was examined in a study aimed at developing more potent and selective integrin antagonists.…”

Section: Linked Di-and Tripeptidesmentioning

confidence: 99%

“…Efforts to design a more conformationally stable molecule began with an inspection of the pliancy of tethers or functional groups. The replacement of a disulfide bridge or a dipeptide in a cyclic peptide with Mamb significantly reduced the flexibility of the overall peptide macrocycle [38]. A structure-activity relationship study was carried out, in which tetrapeptides constrained with Mamb were assayed for their ability to inhibit binding of fibrinogen to the anbß3 receptor [39].…”

Section: Linked Di-and Tripeptidesmentioning

confidence: 99%

Synthesis, Conformational Analysis, and Biological Activity of Proposed Vitronectin Antagonists

Katz¹,

Aubé²

2001

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“…Conformationally constrained cyclopeptides are particularly attractive as designer targets in view of their demonstrated potential to act as regulators of membrane ion-transport, scaffolds in the de novo design of artificial proteins and rigid b-turn templates for the construction of simple mimics of biologically active peptides. [1][2][3][4][5] Among the aminoacids, which are present in cyclopeptides, proline plays an important role. It is found frequently in natu-…”

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confidence: 99%

Design, synthesis, conformational and membrane ion transport studies of proline‐adamantane hybrid cyclic depsipeptides

et al. 2007

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The design, synthesis, conformational, crystallographic, and ion transport studies of 30‐membered, proline containing depsipeptides that incorporate the rigid low molecular weight lipophilic adamantane (Adm) building blocks are reported. The adamantyl groups provide the desired membrane permeability and conformational constraint for efficient transport in lipid membranes. The novel cyclic depsipeptides are: c[AdmC(O)Pro OCH2 CHRNHC(O)ProC(O) AdmC(O)ProC(O)NHCHRCH2 OProC(O)] where RH for A and RCONHAdm for B. Crystal structure analysis of A established that the two peptide segments are identical in formula and in conformation and that the peptides are bonded to the interleaving Adm at the 1 and 3 positions. However, the complete ring is highly asymmetric in shape since bonds for both Peptide‐Adm‐Peptide segments have the syn‐anti motif. Torsional angles for the connecting bonds to Adm are −162°, +71° and −169°, −48°. The irregular clamshell shape of the molecule has three internal CO moieties directed in a manner that could provide three Na+O ligands. While A exhibited negligible transport of Na+ ions across membranes, peptide B endowed with two additional adamantanes in the periphery did transport Na+ ions from outside to inside. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 471–478, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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Template-Constrained Cyclic Peptides: Design of High-Affinity Ligands for GPIIb/IIIa

Cited by 165 publications

References 1 publication

Binding Properties of a Peptide Derived from β-Lactamase Inhibitory Protein

Binding Properties of a Peptide Derived from β-Lactamase Inhibitory Protein

Synthesis, Conformational Analysis, and Biological Activity of Proposed Vitronectin Antagonists

Design, synthesis, conformational and membrane ion transport studies of proline‐adamantane hybrid cyclic depsipeptides

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