Dual Antagonists of Integrins

Nadrah, Kristina; Ms, Dolenc

doi:10.2174/0929867054020882

Cited by 9 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the intense interest in integrins as targets in a range of diseases, , the main strategy to date has been to develop a highly selective antagonist of a single integrin, while the deliberate development of dual antagonists has been little explored, with the exception of the application of α 4 β 1 /α 4 β 7 antagonists in autoimmune disorders . The drive toward selectivity for a single integrin may reduce the effectiveness or safety of the developed antagonists, leaving them vulnerable to the development of resistance or even paradoxical effects, as targeting one receptor promotes the up-regulation of a related receptor binding the same ligand to maintain adhesion and signaling.…”

Section: Integrin Structure and Implications For Drug Developmentmentioning

confidence: 99%

Strategies To Inhibit Tumor Associated Integrin Receptors: Rationale for Dual and Multi-Antagonists

2014

View full text Add to dashboard Cite

The integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions: thrombosis, angiogenesis, and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress toward development of antagonists targeting two or more members of the Arg-Gly-Asp (RGD) binding integrins, notably αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and αIIbβ3, as anticancer therapeutics.

show abstract

Section: Integrin Structure and Implications For Drug Developmentmentioning

confidence: 99%

Strategies To Inhibit Tumor Associated Integrin Receptors: Rationale for Dual and Multi-Antagonists

2014

View full text Add to dashboard Cite

show abstract

“…There are selective fibrinogen and vitronectin receptor antagonists, as well as non-selective antagonists, each with similar affinities for the two integrins, as well as the currently popular dual integrin antagonists [185]. There are selective fibrinogen and vitronectin receptor antagonists, as well as non-selective antagonists, each with similar affinities for the two integrins, as well as the currently popular dual integrin antagonists [185].…”

Section: Arginine Mimetics In the Design Of Antagonists Of Fibrinogenmentioning

confidence: 99%

Arginine Mimetic Structures in Biologically Active Antagonists and Inhibitors

Mašič

2006

CMC

View full text Add to dashboard Cite

Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the arginine moiety in numerous peptidomimetic compounds (thrombin inhibitors, factor Xa inhibitors, factor VIIa inhibitors, integrin receptor antagonists, nitric oxide synthase inhibitors), with the aim of obtaining better activity, selectivity and oral bioavailability.

show abstract

Ein Instrumentarium von αv‐RGD‐Integrin‐Inhibitoren: Wirkstoffsuche, Herausforderungen und Möglichkeiten

et al. 2018

View full text Add to dashboard Cite

Es gibt einen Bedarf an wirksamen und sicheren Pharmazeutika für die Behandlung vernachlässigter Krankheiten, und aktuelle Bestrebungen bei der Suche von Inhibitoren des αv‐RGD‐Integrins zielen in diese Richtung. Allerdings erweist sich die Entwicklung von Wirkstoffen im Bereich der αv‐Integrine aufgrund der sehr ähnlichen Strukturen dieser Rezeptoren und der polaren, zwitterionischen Natur des Pharmakophors als notorisch schwierig. Ziel dieses Aufsatzes ist es, einen Leitfaden für die Wirkstoffsuche in diesem Gebiet anzubieten. Wir tun dies, indem wir hier ein Instrumentarium von αv‐Inhibitoren bestehend aus niedermolekularen Verbindungen (“kleinen Molekülen”) und Antikörpern vorstellen. Niedermolekulare αv‐Verbindungen mit erweiterten Profilen in αvβ1‐, αvβ3‐, αvβ5‐, αvβ6‐ und αvβ8‐Zelladhäsionsassays wurden zusammengetragen, um die Auswahl der richtigen Verbindung für das richtige Experiment zu unterstützen. Dies sollte außerdem helfen, die partiellen Selektivitätsprofile von Verbindungen besser zu verstehen, die in unterschiedlichen Assays unterschiedlicher Forschungsinstitute generiert wurden. Die Perspektiven der zukünftigen Forschung an αv‐Integrinen und die zentral wichtige Targetvalidierung werden diskutiert; fundierte Kenntnisse der Selektivität individueller RGD‐αv‐Integrine sind hier ganz entscheidend. Einblicke in das Design niedermolekularer RGD‐Chemotypen für die topische oder orale Verabreichung werden vorgestellt und klinische Befunde zu fortgeschrittenen Molekülen betrachtet.

show abstract

Dual Antagonists of Integrins

Cited by 9 publications

References 0 publications

Strategies To Inhibit Tumor Associated Integrin Receptors: Rationale for Dual and Multi-Antagonists

Strategies To Inhibit Tumor Associated Integrin Receptors: Rationale for Dual and Multi-Antagonists

Arginine Mimetic Structures in Biologically Active Antagonists and Inhibitors

Ein Instrumentarium von αv‐RGD‐Integrin‐Inhibitoren: Wirkstoffsuche, Herausforderungen und Möglichkeiten

Contact Info

Product

Resources

About