Design and synthesis of a C7 mimetic for the predicted .gamma.-turn conformation found in several constrained RGD antagonists

Jf, Callahan; Jw, Bean; Jl, Burgess; Ds, Eggleston; Hwang, Shin; Kd, Kopple; Pf, Koster; Nichols, Andrew J.; Ce, Peishoff; Jm, Samanen

doi:10.1021/jm00099a027

Cited by 72 publications

(30 citation statements)

References 2 publications

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“…The α v /β 3 and α v /β 5 Integrins bind to RGD ligands in a type IV β-turn, whereas α 2b /β 3 RGD ligands are thought to bind in a type II′ β-turn [24]–[26]. Synthetic mimetics of α 2b /β 3 integrin have RGD ligands in a γ-turn [27]. α 2 /β 1 and likely α 1 /β 1 , α 10 /β 1 , and α 11 /β 1 Integrins binds to the RGD motif in a collagen triple helix [28].…”

Section: Introductionmentioning

confidence: 99%

Secondary Structure, a Missing Component of Sequence-Based Minimotif Definitions

et al. 2012

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Minimotifs are short contiguous segments of proteins that have a known biological function. The hundreds of thousands of minimotifs discovered thus far are an important part of the theoretical understanding of the specificity of protein-protein interactions, posttranslational modifications, and signal transduction that occur in cells. However, a longstanding problem is that the different abstractions of the sequence definitions do not accurately capture the specificity, despite decades of effort by many labs. We present evidence that structure is an essential component of minimotif specificity, yet is not used in minimotif definitions. Our analysis of several known minimotifs as case studies, analysis of occurrences of minimotifs in structured and disordered regions of proteins, and review of the literature support a new model for minimotif definitions that includes sequence, structure, and function.

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Section: Introductionmentioning

confidence: 99%

Secondary Structure, a Missing Component of Sequence-Based Minimotif Definitions

et al. 2012

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“…To test this conformational features, γ-turn mimetics were incorporated at the Asp level in nonpeptide analogues. After initial attempts with 2-azepinones [70], extensive investigations on differently substituted 1,4-benzodiazepine non-peptide analogues were carried out. Several potent peptidomimetics were discovered, as exemplified here by the orally active α IIb β 3 antagonist 13 [71,72].…”

Section: β-Turn-based Peptidomimetics As Antagonists Of Integrinsmentioning

confidence: 99%

Modulation of Protein-Protein Interactions by Stabilizing/Mimicking Protein Secondary Structure Elements

Vega

Martı́n-Martı́nez²,

González‐Muñiz

2007

CTMC

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In view of the crucial role of protein-protein intercommunication both in biological and pathological processes, the search of modulators of protein-protein interactions (PPIs) is currently a challenging issue. The development of rational strategies to imitate key secondary structure elements of protein interfaces is complementary to other approaches based on the screening of synthetic or virtual libraries. In this sense, the present review provides representative examples of compounds that are able to disturb PPIs of therapeutic relevance, through the stabilization or the imitation of peptide hot-spots detected in contact areas of the interacting proteins. The review is divided into three sections, covering mimetics of the three main secondary structural elements found in proteins, in general, and in protein-protein interfaces, in particular (alpha-helices, beta-sheets, and reverse turns). Once the secondary element has been identified, the first approach typically involves the translation of the primary peptide structure into different cyclic analogues. This is normally followed by gradual decrease of the peptide nature through combination of peptide and non-peptide fragments in the same molecule. The final step usually consists in the development of pertinent organic scaffolds for appending key functional groups in the right spatial disposition, as a means towards totally non-peptide small molecule PPI modulators.

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“…The first step was the development of peptidomimetic structures that resemble the peptides mentioned above by a combination of molecular modelling and screening approaches. Many such compounds with a variety of structures are now known [45], and many of them are in various stages of clinical testing. A characteristic that seems to be essential for both specificity and avidity is the doubly charged zwitterionic structure found in RGD (or KGD) with the positive charge of the arginine (or lysine) and the negative charge of the aspartic acid separated by a specific distance.…”

Section: Development Of Inhibitors Targeted At Platelet Integrins As mentioning

confidence: 99%

Integrins and cardiovascular disease

Clemetson¹,

Clemetson²

1998

Cellular and Molecular Life Sciences (CMLS)

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Cardiovascular diseases involve abnormal cell-cell interactions leading to the development of atherosclerotic plaque, which when ruptured causes massive platelet activation and thrombus formation. Parts of a loose thrombus may detach to form an embolus, blocking circulation at a more distant point. The integrins are a family of adhesive cell receptors interacting with adhesive proteins or with counterreceptors on other cells. There is now solid evidence that the major integrin on platelets, the fibrinogen receptor alpha IIb beta 3, has an important role in several aspects of cardiovascular diseases and that its regulated inhibition leads to a reduction in incidence and mortality due to these disorders. The development of alpha IIb beta 3 inhibitors is an important strategy of many pharmaceutical companies which foresee a large market for the treatment of acute conditions in surgery, the symptoms of chronic conditions and, it is hoped, maybe even the successful prophylaxis of these conditions. Although all the associated problems have not been solved, the undoubted improvements in patient care resulting from the first of these treatments in the clinic have stimulated further research on the role of integrins on other vascular cells in these processes and in the search for new inhibitors. Both the development of specific inhibitors and of mice with specific integrin subunit genes ablated have contributed to a better understanding of the function of integrins in development of the cardiovascular system.

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Design and synthesis of a C7 mimetic for the predicted .gamma.-turn conformation found in several constrained RGD antagonists

Cited by 72 publications

References 2 publications

Secondary Structure, a Missing Component of Sequence-Based Minimotif Definitions

Secondary Structure, a Missing Component of Sequence-Based Minimotif Definitions

Modulation of Protein-Protein Interactions by Stabilizing/Mimicking Protein Secondary Structure Elements

Integrins and cardiovascular disease

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