The alpha(V)beta(3) integrin receptor plays an important role in human tumor metastasis and tumor-induced angiogenesis. The in vivo inhibition of this receptor by antibodies or by cyclic peptides containing the RGD sequence may in the future be used to selectively suppress these diseases. Here we investigate the influence of N-methylation of the active and selective alpha(V)beta(3) antagonist cyclo(RGDfV) (L1) on biological activity. Cyclo(RGDf-N(Me)V-) (P5) was found to be even more active than L1 and is one of the most active and selective compounds in inhibiting vitronectin binding to the alpha(V)beta(3) integrin. Its high-resolution, three-dimensional structure in water was determined by NMR techniques, distance geometry calculations, and molecular dynamics calculations, providing more insight into the structure-activity relationship.

N-Methylated cyclic RGD peptides as highly active and selective alpha(V)beta(3) integrin antagonists.

Protein–protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding molecules that are generally referred to as peptidomimetics Herein, we introduce a new classification of peptidomimetics (classes A–D) that enables a clear assignment of available approaches Based on this classification, the Review summarizes strategies that have been applied for the structure-based design of PPI inhibitors through stabilizing or mimicking turns, β-sheets, and helices

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.201412070

Structure-Based Design of Inhibitors of Protein-Protein Interactions: Mimicking Peptide Binding Epitopes

Cilengitide, a cyclic RGD pentapeptide, is currently in clinical phase III for treatment of glioblastomas and in phase II for several other tumors This drug is the first anti-angiogenic small molecule targeting the integrinsv� 3, � v� 5 and � 5� 1 It was developed by us in the early 90s by a novel procedure, the spatial screening This strategy resulted in c(RGDfV), the first superactivev� 3 inhibitor (100 to 1000 times increased activity over the linear reference peptides), which in addition exhibited high selectivity against the platelet receptorIIb�3 This cyclic peptide was later modified by N-methylation of one peptide bond to yield an even greater antagonistic activity in c(RGDf(NMe)V) This peptide was then dubbed Cilengitide and is currently developed as drug by the company Merck-Serono (Germany) This article describes the chemical development of Cilengitide, the biochemical background of its activity and a short review about the present clinical trials The positive anti-angiogenic effects in cancer treatment can be further increased by combination with "classical" anti-cancer therapies Several clinical trials in this direction are under investigation

/pdf/cilengitide-the-first-anti-angiogenic-small-molecule-drug-2n5x570zs9.pdf

Cilengitide: The First Anti-Angiogenic Small Molecule Drug Candidate. Design, Synthesis and Clinical Evaluation

The αVβ3 integrin is implicated in human tumor metastasis and in angiogenesis. The design of low-molecular-mass αVβ3 antagonists by “spatial screening” led to the highly active peptides c(RGDFV) and c(RGDFV). Here the influence of the amino acids in positions 4 and 5 flanking the RGD-sequence on the inhibition of vitronectin and fibrinogen binding to the isolated αVβ3 and αIIbβ3 receptors was investigated. The influence of the side chain and the backbone conformation on activity and selectivity was studied. The compounds were divided into conformational classes. For each class at least one representative peptide was subjected to detailed structure determination in solution. The peptides of classes 1, 2, and 3 show a βII‘/γ-turn arrangement with the d-amino acid in the i + 1 position of the βII‘-turn. By contrast, the peptides of class 4 reveal a modified βII‘/γ-turn pattern with glycine in the i + 1 position of the βII‘-turn and the d-amino acid in the i + 1 position of the γ-turn. Class 1 is divided into...

Structural and Functional Aspects of RGD-Containing Cyclic Pentapeptides as Highly Potent and Selective Integrin αVβ3 Antagonists

Polymer micelles are rapidly becoming a powerful nanomedicine platform for cancer therapeutic applications due to their small size (10-100 nm), in vivo stability, ability to solubilize water insoluble anticancer drugs, and prolonged blood circulation times. Recent data from clinical trials with three micelle formulations have highlighted these and other pharmacokinetic advantages with reduced systemic toxicity and patient morbidity compared to conventional drug formulation. While the initial anti-tumor efficacy of these systems seems promising, a strong research impetus has been placed on micelle functionalization in order to achieve tumor targeting and site-specific drug release, with the hope of reaching a more pronounced tumor response. Hence, the purpose of this review is to draw attention to the new developments of multi-functional polymer micelles for cancer therapy with special focus on tumor targeting and controlled drug release strategies.

Functionalized Micellar Systems for Cancer Targeted Drug Delivery

The cyclic pentapeptide cyclo(-Arg-Gly-Asp-d-Phe-Val-) is a highly potent and selective inhibitor for the αvβ3 integrin and is a prospective anticancer drug by acting to inhibit angiogenesis and by...

Stereoisomerism and Biological Activity of the Selective and Superactive αvβ3 Integrin Inhibitor cyclo(-RGDfV-) and Its Retro-Inverso Peptide

Integrins play a major role in cell-cell and cell-matrix interactions. The majority of the different types of integrins recognize the tripeptide sequence arginine-glycine-aspartic acid (RGD). To explore the spatial requirements of the pharmacophore for receptor selectivity and high activity, a new procedure, ‘spatial screening’, was used. The procedure is based on the experience that the conformation of small cyclic peptides is mainly determined by the chirality of the amino acids (and glycine or proline). For example, cyclic pentapeptides with one d and four l amino acids prefer a βII'/γ conformation. The sequence RGDFV was shifted around this spatial βII'/γ template by synthesis of five peptides in which one of the amino acids was used in d-configuration. It turned out that cyclo(-RGDfV-) is a selective inhibitor for the αvβ3 integrin, which is strongly expressed in cancer cells. Systematic variations with different turn mimetics, retro-inverso structures, modified peptide bonds and sugar amino acids are discussed.

Design of superactive and selective integrin receptor antagonists containing the RGD sequence

The invention relates to novel cyclopeptides of the formula I cyclo-(Arg-B-Asp-D-E) I in which B, D, and E have the meanings defined herein, and their salts. These compounds act as integrin inhibitors and can be used, in particular, for the prophylaxis and treatment of disorders of the circulation and in tumor therapy.

Cyclic peptides containing Arg-Gly-Asp, and derivatives thereof, as adhesion inhibitors

The invention relates to novel cyclopeptides of the formula I cyclo-(Arg-B-Asp-D-E) I in which B, D and E have the meaning given in Claim 1, and their salts. These compounds act as integrin inhibitors and can be used in particular for the prophylaxis and treatment of disorders of the circulation and in tumour therapy.

Cyclic adhesions inhibitors

Recent progress in the field of αv-integrin antagonists

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Jochen Wermuth

Author Tools

Chat about Author