Non-Peptide Fibrinogen Receptor Antagonists. 7. Design and Synthesis of a Potent, Orally Active Fibrinogen Receptor Antagonist

Duggan, Mark E.; Naylor-Olsen, Adel M.; Perkins, James J.; Anderson, Paul S.; Chang, Charles T. C.; Cook, Jacquelynn J.; Gould, Robert J.; Ihle, Nathan C.; Hartman, George D.

doi:10.1021/jm00017a017

Cited by 62 publications

(45 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In keeping with the general guidelines found above, hydrophobic and aromatic tethers incorporated into cyclic RGD peptides increase their affinity [41]. Most amino acid residues that have been shown to increase affinity or potency are those which are highly enriched at protein-protein interaction sites, including Asp, Arg and Tyr, and have, in addition, bulky aromatic groups such as Trp.…”

Section: F Inhibitors Of Integrin-ligand Inter-actions Based On Intementioning

confidence: 61%

Design and Structure of Peptide and Peptidomimetic Antagonists of Protein- Protein Interaction

Sillerud¹,

Larson

2005

CPPS

118

View full text Add to dashboard Cite

Peptides based on the amino acid sequences found at protein-protein interaction sites make excellent leads for antagonist development. A statistical picture of amino acids involved in protein-protein interactions indicates that proteins recognize and interact with one another through the restricted set of specialized interface amino acid residues, Pro, Ile, Tyr, Trp, Asp and Arg. These amino acids represent residues from each of the three classes of amino acids, hydrophobic, aromatic and charged, with one anionic and one cationic residue at neutral pH. The use of peptides as drug leads has been successfully used to search for antagonists of cell-surface receptors. Peptide, peptidomimetic, and non-peptide organic inhibitors of a class of cell surface receptors, the integrins, currently serve as therapeutic and diagnostic imaging agents. In this review, we discuss the structural features of protein-protein interactions as well as the design of peptides, peptidomimetics, and small organic molecules for the inhibition of protein-protein interactions. Information gained from studying inhibitors of integrin functions is now being applied to the design and testing of inhibitors of other protein-protein interactions. Most drug development progress in the past several decades has been made using the enzyme binding-pocket model of drug targets. Small molecules are designed to fit into the substrate-binding pockets of proteins based on a lock-and-key, induced-fit, or conformational ensemble model of the protein binding site. Traditionally, enzymes have been used as therapeutic drug targets because it was easier to develop rapid, sensitive screening assays, and to find low molecular weight inhibitors that blocked the active site. However, for proteins which interact with other proteins, rather than with small substrate molecules, the lack of binding pockets means that this approach will not generally succeed. There exist many diseases in which the inhibition of protein-protein interactions would provide therapeutic benefit, but there are no general methods available to address such problems. The focus of the first part of this review is to discuss the features of protein-protein interactions which may serve as general guidelines for the development and design of inhibitors for protein-protein interactions. In the second part we focus on the design of peptides (lead compounds) and their conversion into peptidomimetics or small organic molecules for the inhibition of protein-protein interactions. We draw examples from the important and emerging area of integrin-based cell adhesion and show how the principles of protein-protein interactions are followed in the discovery, optimization and usage of specific protein interface peptides as drug leads.

show abstract

Section: F Inhibitors Of Integrin-ligand Inter-actions Based On Intementioning

confidence: 61%

Design and Structure of Peptide and Peptidomimetic Antagonists of Protein- Protein Interaction

Sillerud¹,

Larson

2005

CPPS

118

View full text Add to dashboard Cite

show abstract

“…Over the past years, various types of disulfide-based cyclic RGD peptides have been reported 16–27. Recently, an internalizing disulfide bond-containing RGD peptide, called iRGD , has been developed to enhance both cancer detection and treatment by deep tissue penetration.…”

mentioning

confidence: 99%

Exploring new near-infrared fluorescent disulfide-based cyclic RGD peptide analogs for potential integrin-targeted optical imaging

Nikiforovich

et al. 2011

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

We synthesized disulfide-based cyclic RGD pentapeptides bearing a near-infrared fluorescent dye (cypate), represented by cypate-c(CRGDC) (1) for integrin-targeted optical imaging. These compounds were compared with the traditional lactam-based cyclic RGD counterpart, cypatec(RGDfK) (2). Molecular modeling suggests that the binding affinity of 2 to integrin α v β 3 is an order of magnitude higher than that of 1. This was confirmed experimentally, which further showed that substitution of Gly with Pro, Val and Tyr in 1 remarkably hampered the α v β 3 binding. Interestingly, cell microscopy with A549 cells showed that 1 exhibited higher cellular staining than 2. These results indicate that factors other than receptor binding affinity to α v β 3 dimeric proteins mediate cellular uptake. Consequently, 1 and its analogs may serve as valuable molecular probes for investigating the selectivity and specificity of integrin targeting by optical imaging. KeywordsDisulfide-based cyclization; RGD peptide; integrin α v β 3 binding; Near-infrared fluorescent probe; Optical imagingThe RGD (arginine-glycine-aspartic acid) tripeptide motif plays an essential role in the molecular recognition of integrin α v β 3 and some other integrin subtypes. [1][2][3][4][5][6] The overexpression of integrin α v β 3 found in various types of tumors and neo-vasculatures and this dimeric protein complex is involved in regulating tumor growth, angiogenesis, and metastasis. Therefore, RGD-based integrin α v β 3 targeting has provided an effective approach for improving tumor imaging, and drug delivery. Cyclic RGD compounds such as the conventional lactam-based cyclic pentapeptide c(RGDfK) (where "f" represents Dphenylalanine) exhibit remarkable binding affinity and selectivity for integrin α v β 3 . 7-9 For * Corresponding author. Fax: +1 314-747-5191, achilefus@mir.wustl.edu (S. Achilefu), Homepage: http:/www.orl.wustl.edu. † Present address: MolLife Design LLC, St. Louis, MO, USA Supplementary data Supplementary data associated with this article can be found in the online version.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Despite some promising results, many aspects of integrin targeting, tumor imaging, and therapy that employ RGD peptides remain unclear. 13 In particular, integrins have 24 subtypes through different combinations of α and β subunits. 14, 15 Therefore, it is important to explore novel integrin-targeted ligands that are distinguishable from c(RGDfK) in structure as well as in receptor binding selectivity and specificity. We envision that such compounds with different structural a...

show abstract

“…L-734 217 and 3 H-L-734 217 ( Figure 1) were synthesized at Merck Research Laboratories, West Point, PA. 25,27 Pentobarbital sodium and epinephrine were obtained from Anpro Pharmaceutical (Arcadia, CA) and Parke-Davis (Morris Plains, NJ), respectively. ADP and collagen were purchased from Chrono-Log Co. (Havertown, PA).…”

Section: Chemicalsmentioning

confidence: 99%

“…25,26 In view of the above background information, we investigated the eects of pentobarbital on the pharmacokinetics and pharmacodynamics of L-734 217. For a better understanding of L-734 217 pharmacokinetic characteristics, studies on in vivo metabolism and elimination as well as in vitro protein binding and blood distribution of L-734 217 also were carried out.…”

Section: Introductionmentioning

confidence: 99%

Effects of pentobarbital on pharmacokinetics and pharmacodynamics of a potent fibrinogen receptor antagonist, L-734 217, in dogs

Prueksaritanont

Stranieri

Hand

et al. 1997

Biopharm. Drug Dispos.

View full text Add to dashboard Cite

Non-Peptide Fibrinogen Receptor Antagonists. 7. Design and Synthesis of a Potent, Orally Active Fibrinogen Receptor Antagonist

Cited by 62 publications

References 21 publications

Design and Structure of Peptide and Peptidomimetic Antagonists of Protein- Protein Interaction

Design and Structure of Peptide and Peptidomimetic Antagonists of Protein- Protein Interaction

Exploring new near-infrared fluorescent disulfide-based cyclic RGD peptide analogs for potential integrin-targeted optical imaging

Effects of pentobarbital on pharmacokinetics and pharmacodynamics of a potent fibrinogen receptor antagonist, L-734 217, in dogs

Contact Info

Product

Resources

About