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Order Rowavirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
Wickham et al. (1997) provided fiber protein with one of the targeting motifs that was known to interact with high affinity to the αv-integrins or to heparin sulfate proteoglycans. One motif contained an RGD integrin-binding sequence, ACDCRGDCFCG, while the other was a string of seven lysine residues KKKKKKK that contained multiple overlapping consensus motifs that allowed high-affinity binding to heparin and heparan sulfate. The use of the RGD motif within the fiber protein was optimized by Reynolds et al. (1999) and later by Lavilla-Alonso et al. (2010). It should be noted here that the introduction of the RGD motif into the fiber protein was successfully used to enhance the mucosal immunogenicity of the nonhuman primate-based AdV-C7 platform (Krause et al. 2013).
The Labeling of Peptides with Positron-Emitting Radionuclides: The Importance of PET in Cancer Diagnosis
Published in Marco Chinol, Giovanni Paganelli, Radionuclide Peptide Cancer Therapy, 2016
Stefano Papi, Nicoletta Urbano, Esteban R. Obenaus, Marco Chinol
Integrins are transmembrane glycoproteins consisting of two subunits, α and β, and to date, 25 different integrin αβ heterodimers have been reported. Integrins mediate cell adhesion to the extracellular matrix proteins or to the surfaces of other cells. Among the integrins, the αVβ3 receptor, also known as the vitronectin receptor, has been reported to be involved in tumor cell migration. The αVβ3 receptors are expressed on metastatic tumor cells and are involved in angiogenesis. Thus, the αVβ3 integrin participates in tumor metastasis and tumor-related angiogenesis. Angiogenesis, or formation of new blood vessels, is crucial for the growth of tumors from a few millimeters spots to bulky masses. In this highly regulated process, over the surface of endothelial cells is associated an overexpression of the integrin αVβ3. Characteristic of integrins is the recognition of the arginine-glicine-aspartic acid (RGD) motif. Therefore, another field in tumor imaging has been and currently is the labeling of RGD-type molecules to study the extention ofangiogenesis.
Human Metapneumovirus Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Jennifer Elana Schuster, John V. Williams
The F protein contains a conserved arginine–glycine–aspartate (RGD) motif. MPV engages the subset of RGD-binding integrins, including α5β1, αVβ1, and αVβ5, to attach to and enter cells. When RGD-binding integrins are blocked, virus binding is diminished by approximately 50%, but infection is reduced by 90%, suggesting that although integrins are necessary for efficient infection, other receptors may be present.19,20 The G protein binds to heparan and glycosaminoglycans.21
Computational approaches for the design of modulators targeting protein-protein interactions
Published in Expert Opinion on Drug Discovery, 2023
Ashfaq Ur Rehman, Beenish Khurshid, Yasir Ali, Salman Rasheed, Abdul Wadood, Ho-Leung Ng, Hai-Feng Chen, Zhiqiang Wei, Ray Luo, Jian Zhang
The application of p53 and bcl2 notions to tissue engineering is as simple as finding naturally existing binding modalities and integrin-ECM interactions. This could lead to the discovery of new integrin-binding peptide motifs and chemical compounds. The RGD motif has been computationally and experimentally explored, because it binds a variety of integrin types. However, discrepancies in binding and recognition were caused by the motif internal structure and binding mechanism [166,167]. A scaffold with an RGD motif may adopt conformations that are recognized by a subset of integrins. A small molecule antagonist (i.e. RUC-1) was created using theoretical and experimental methods [168]. The RUC-1 antagonist binds to the IIb3 integrin without changing its shape [169]. Other computational algorithms aim to improve the peptide epitopes of membrane proteins like integrins [170]. The synthesis of material that self-assembles to act as a scaffold for cells is a second focus. To localize a drug to a specific physiological site, self-assembling peptides that can form hydrogels after injection into a patient are commonly employed [171].
Overcoming challenges in developing small molecule inhibitors for GPVI and CLEC-2
Published in Platelets, 2021
Foteini-Nafsika Damaskinaki, Luis A. Moran, Angel Garcia, Barrie Kellam, Steve P. Watson
The RGD motif has inspired the development of RGD mimetics to contain bioisosteres of endogenous components of the RGD sequence, with enhanced physicochemical properties and re-engineered conformation. The common short peptide RGD and the conformational flexibility of the RGD motif determines affinity and integrin sub-type selectivity. The development of RGD mimetics has also benefitted from the discovery of RGD-containing natural peptides, which later allowed the cyclization of RGD-containing peptides to increase the affinity and selectivity. Sequences with slight variations in the RGD-motif have also been successful, such as the cyclic heptapeptide, eptifibatide, derived from a snake venom with a Lys-Gly-Asp (KGD) sequence [50]. Non-peptide, small-molecule inhibitors based on the RGD motif have also been developed. Chemical optimization of known RGD-mimetics has led to the discovery of other structures with comparable potency, such as tirofiban with tyrosine as a backbone [51]. Eptifibatide and tirofiban are used in the clinic for the treatment of acute thrombosis [51,52]. Advances on chemical optimization have also led the design of prodrugs that are orally available. Lotrafiban is an orally available RGD mimetic prodrug that reached phase III of clinical trials, but did not proceed further due to excessive bleeding [53,54]. Nevertheless, this demonstrates that it is possible to develop potent, orally available inhibitors against PPIs, at least when there is a major epitope in the receptor.
MDA-7/interleukin 24 (IL-24) in tumor gene therapy: application of tumor penetrating/homing peptides for improvement of the effects
Published in Expert Opinion on Biological Therapy, 2019
Mohammad Rasoolian, Majid Kheirollahi, Seyed Younes Hosseini
The peptides such as RGD, RGR, and NGR are well-defined THPs that mediate the translocation of gene cargo following endocytosis (Figure 4) [66,80]. There are different RGD derived peptides including RGD4C (standard cyclic), tRGD (truncated form), cyclic peptide cyclo (RGDf[NMe]V) or CilengitideTM, iRGD, and RGD10 that have a similar affinity to integrins and pattern of entry. The iRGD, as an example, consists of three independent parts including a tumor homing motif (RGD), an R/KXXR/K tumor penetrating motif, and a protease recognition site. The specified RGD-mediated cargo penetration into the target cell occurs in three steps. In the first step, the exposed RGD motif can bind to specific integrin on the tumor vascular endothelium and consequently concentrate around the tumor microenvironment. Then, the penetrating motif is exposed following the action of undefined protease. This motif designated as C-end rule motif (CendR motif) is located at the carboxyl-termini and activated by proteolysis inside the tumor environment. In the end, exposed CendR motif binds to neuropilin-1 (NRP-1) and accesses the cytoplasmic substrate through an endocytosis penetration pathway [67,86]. Therefore, following a specific trafficking to tumor vessels that is not achievable by CPPs, THPs-cargo can extravasate precisely and concentrate around the tumor tissue.