Arginylglycylaspartic acid: Difference between revisions

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 428801909

| ImageFile = Arginylglycylaspartic acid.png

| ImageFile_Ref = {{chemboximage|correct|??}}

| ImageName = Stereo, skeletal formula of arginylglycylaspartic acid

| SystematicName=(2''S'')-2-<nowiki>[[</nowiki>2-<nowiki>[[</nowiki>(2''S'')-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]butanedioic acid

| OtherNames=<small>L</small>-Arginyl-Glycyl-<small>L</small>-Aspartic acid; Arg-Gly-Asp

| Abbreviations = RGD Peptide{{citation needed|date=July 2012|reason=To confirm that this is a nonproprietary abbreviation for this substance.}}

| CASNo = 99896-85-2

| CASNo_Ref = {{cascite|correct|??}}

| CASNo_Comment =

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 78VO7F77PN

| PubChem = 3328704

| PubChem1 = 104802

| PubChem1_Comment =

| ChemSpiderID = 2575945

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID1 = 94603

| ChemSpiderID1_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID1_Comment =

| MeSHName = arginyl-glycyl-aspartic+acid

| ChEMBL = 313763

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| SMILES = C(C[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)O)N)CN=C(N)N

| StdInChI = 1S/C12H22N6O6/c13-6(2-1-3-16-12(14)15)10(22)17-5-8(19)18-7(11(23)24)4-9(20)21/h6-7H,1-5,13H2,(H,17,22)(H,18,19)(H,20,21)(H,23,24)(H4,14,15,16)

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = IYMAXBFPHPZYIK-UHFFFAOYSA-N

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

}}

| C=12 | H=22 | N=6 | O=6

| LogP = −3.016

| pKa = 2.851

| pKb = 11.146

}}

|Section3={{Chembox Related

| OtherCompounds =

}}

'''Arginylglycylaspartic acid''' ('''RGD''') is the most common [[peptide]] [[Short linear motif|motif]] responsible for [[cell adhesion]] to the [[extracellular matrix]] (ECM), found in species ranging from ''[[Drosophila melanogaster|Drosophila]]'' to humans. Cell adhesion proteins called [[integrins]] recognize and bind to this sequence, which is found within many matrix proteins, including [[fibronectin]], [[fibrinogen]], [[vitronectin]], [[osteopontin]], and several other adhesive extracellular matrix proteins.<ref name=":14">{{Cite journal|last1=Plow|first1=Edward F.|last2=Haas|first2=Thomas A.|last3=Zhang|first3=Li|last4=Loftus|first4=Joseph|last5=Smith|first5=Jeffrey W.|date=2000-07-21|title=Ligand Binding to Integrins|journal=Journal of Biological Chemistry|language=en|volume=275|issue=29|pages=21785–21788|doi=10.1074/jbc.R000003200|issn=0021-9258|pmid=10801897|doi-access=free}}</ref> The discovery of RGD and elucidation of how RGD binds to integrins has led to the development of a number of drugs and diagnostics,<ref name=":11" /> while the peptide itself is used ubiquitously in [[bioengineering]].<ref name=":6" /> Depending on the application and the integrin targeted, RGD can be chemically modified or replaced by a similar peptide which promotes cell adhesion.

== Discovery ==

RGD was identified as the minimal recognition sequence within [[fibronectin]] required for cell attachment by Ruoslahti and Pierschbacher in the early 1980s. To do this, the authors synthesized various peptides based on the hypothesized cell attachment site of fibronectin. They then coupled those peptides to protein-coated plastic and tested each for cell attachment-promoting activity. Only those that contained the RGD sequence were found to enhance cell attachment. Further, they showed that peptides containing RGD were able to inhibit cell attachment to fibronectin-coated substrates, whereas peptides not containing RGD did not.<ref>{{Cite journal|last1=Pierschbacher|first1=Michael D.|last2=Ruoslahti|first2=Erkki|date=1984-05-03|title=Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule|journal=Nature|language=en|volume=309|issue=5963|pages=30–33|bibcode=1984Natur.309...30P|doi=10.1038/309030a0|pmid=6325925|s2cid=4371931}}</ref>

These foundational studies also identified the cellular receptors that recognize the sequence. These studies utilized a synthetic RGD-containing peptide to isolate the putative receptors, and then demonstrated that [[liposome]]s containing the isolated proteins could bind to fibronectin, in much the same way as cells with surface receptors.<ref>{{Cite journal|last1=Pytela|first1=Robert|last2=Pierschbacher|first2=Michael D.|last3=Ruoslahti|first3=Erkki|year=1985|title=Identification and isolation of a 140 kd cell surface glycoprotein with properties expected of a fibronectin receptor|journal=Cell|volume=40|issue=1|pages=191–198|doi=10.1016/0092-8674(85)90322-8|pmid=3155652|s2cid=21777919}}</ref><ref>{{Cite journal|last1=Pytela|first1=R.|last2=Pierschbacher|first2=M. D.|last3=Ginsberg|first3=M. H.|last4=Plow|first4=E. F.|last5=Ruoslahti|first5=E.|date=1986-03-28|title=Platelet membrane glycoprotein IIb/IIIa: member of a family of Arg-Gly-Asp--specific adhesion receptors|journal=Science|language=en|volume=231|issue=4745|pages=1559–1562|bibcode=1986Sci...231.1559P|doi=10.1126/science.2420006|issn=0036-8075|pmid=2420006}}</ref> The discovered receptors were later named integrins.<ref>{{Cite journal|last=Hynes|first=R|title=Integrins: A family of cell surface receptors|journal=Cell|volume=48|issue=4|pages=549–554|doi=10.1016/0092-8674(87)90233-9|year=1987|pmid=3028640|s2cid=27274629}}</ref><ref>{{Cite journal|last1=Ruoslahti|first1=E.|last2=Pierschbacher|first2=M. D.|date=1987-10-23|title=New perspectives in cell adhesion: RGD and integrins|journal=Science|language=en|volume=238|issue=4826|pages=491–497|doi=10.1126/science.2821619|issn=0036-8075|pmid=2821619|bibcode=1987Sci...238..491R}}</ref> The RGD motif is presented in slightly different ways in different proteins, making it possible for the many RGD-binding integrins to selectively distinguish individual adhesion proteins.<ref>{{Cite journal|last1=Pierschbacher|first1=M. D.|last2=Ruoslahti|first2=E.|date=1987-12-25|title=Influence of stereochemistry of the sequence Arg-Gly-Asp-Xaa on binding specificity in cell adhesion.|url=http://www.jbc.org/content/262/36/17294|journal=Journal of Biological Chemistry|language=en|volume=262|issue=36|pages=17294–17298|doi=10.1016/S0021-9258(18)45376-8|issn=0021-9258|pmid=3693352|doi-access=free}}</ref><ref>{{Cite journal|last=Humphries|first=M. J.|date=1990-12-01|title=The molecular basis and specificity of integrin-ligand interactions|url=http://jcs.biologists.org/content/97/4/585|journal=Journal of Cell Science|language=en|volume=97|issue=4|pages=585–592|doi=10.1242/jcs.97.4.585|issn=0021-9533|pmid=2077034}}</ref>

== Use in drug discovery ==

Understanding of the molecular basis of binding to integrins has enabled the development of several drugs for cardiovascular disease and cancer, including [[eptifibatide]], [[tirofiban]] and [[cilengitide]].<ref>{{Cite journal|title=Cilengitide: The First Anti-Angiogenic Small Molecule Drug Candidate. Design, Synthesis and Clinical Evaluation|journal=[[Anti-Cancer Agents in Medicinal Chemistry]]|last3=Kessler|first1=Carlos|last1=Mas-Moruno|first2=Florian|last2=Rechenmacher|first3=Horst|year=2010|doi=10.2174/187152010794728639|volume=10|issue=10|pages=753–768|authorlink3=Horst Kessler|pmid=21269250|pmc=3267166}}</ref><ref name=":11">{{Cite journal|last1=Ley|first1=Klaus|last2=Rivera-Nieves|first2=Jesus|last3=Sandborn|first3=William J.|last4=Shattil|first4=Sanford|title=Integrin-based therapeutics: biological basis, clinical use and new drugs|journal=Nature Reviews Drug Discovery|volume=15|issue=3|pages=173–183|doi=10.1038/nrd.2015.10|pmid=26822833|pmc=4890615|year=2016}}</ref> These drugs inhibit integrin binding. PET radiotracers such as fluciclatide utilize RGD-containing peptides to home to tumors, allowing for cancer monitoring.<ref name=":0">{{Cite journal|last1=Battle|first1=Mark R.|last2=Goggi|first2=Julian L.|last3=Allen|first3=Lucy|last4=Barnett|first4=Jon|last5=Morrison|first5=Matthew S.|date=2011-03-01|title=Monitoring Tumor Response to Antiangiogenic Sunitinib Therapy with ¹⁸F-Fluciclatide, an ¹⁸F-Labeled αVβ3-Integrin and αVβ5-Integrin Imaging Agent|journal=Journal of Nuclear Medicine|language=en|volume=52|issue=3|pages=424–430|doi=10.2967/jnumed.110.077479|issn=0161-5505|pmid=21321268|doi-access=free}}</ref>

=== Cardiovascular disease ===

[[File:Eptifibatide structure.svg|thumb|267x267px|Structure Eptifibatide, a cyclic, RGD-mimetic antiplatelet drug.]]

[[Eptifibatide]] and tirofiban are anti-clotting drugs indicated to prevent thrombosis in acute ischemic coronary syndromes.<ref name=":2">{{Cite journal|last1=Zeymer|first1=Uwe|last2=Wienbergen|first2=Harm|date=2007-12-01|title=A Review of Clinical Trials with Eptifibatide in Cardiology|journal=Cardiovascular Drug Reviews|language=en|volume=25|issue=4|pages=301–315|doi=10.1111/j.1527-3466.2007.00022.x|pmid=18078431|issn=1527-3466|doi-access=free}}</ref><ref>{{Cite journal|last=Kloner|first=Robert A.|date=2013-08-02|title=Current State of Clinical Translation of Cardioprotective Agents for Acute Myocardial Infarction|journal=Circulation Research|language=en|volume=113|issue=4|pages=451–463|doi=10.1161/circresaha.112.300627|issn=0009-7330|pmid=23908332|doi-access=free}}</ref> Eptifibatide is additionally FDA approved for patients undergoing [[percutaneous coronary intervention]].<ref>{{Cite journal|last1=King|first1=Shawn|last2=Short|first2=Marintha|last3=Harmon|first3=Cassidy|date=2016-03-01|title=Glycoprotein IIb/IIIa inhibitors: The resurgence of tirofiban|url=https://www.sciencedirect.com/science/article/pii/S1537189115001573|journal=Vascular Pharmacology|language=en|volume=78|pages=10–16|doi=10.1016/j.vph.2015.07.008|pmid=26187354|issn=1537-1891}}</ref> These drugs block activation of the integrin responsible for aggregation of [[platelet]]s (αIIbβ3, also known as [[glycoprotein IIb/IIIa]]) in response to the blood glycoproteins [[fibrinogen]] and [[von Willebrand factor]]. Eptifibatide (marketed as Integrilin) is a cyclic (circular) seven amino acid peptide, whereas tirofiban is a small molecule designed to mimic the chemistry and binding affinity of the RGD sequence.<ref name=":10" /><ref>{{Cite journal|last1=Hashemzadeh|first1=Mehrnoosh|last2=Furukawa|first2=Matthew|last3=Goldsberry|first3=Sarah|last4=Movahed|first4=Mohammad Reza|date=2008|title=Chemical structures and mode of action of intravenous glycoprotein IIb/IIIa receptor blockers: A review|journal=Experimental & Clinical Cardiology|volume=13|issue=4|pages=192–197|issn=1205-6626|pmc=2663484|pmid=19343166}}</ref>

=== Cancer ===

[[Cilengitide]], a cyclic pentapeptide (RGDfV), is an investigational drug intended to block the growth of new blood vessels in tumors by interfering with the activation of [[Alpha-v beta-3|integrin αVβ3]].<ref name=":3">{{Cite journal|last1=Mas-Moruno|first1=Carlos|last2=Rechenmacher|first2=Florian|last3=Kessler|first3=Horst|date=2010-12-01|title=Cilengitide: The First Anti-Angiogenic Small Molecule Drug Candidate. Design, Synthesis and Clinical Evaluation|url=https://www.ingentaconnect.com/content/ben/acamc/2010/00000010/00000010/art00007|journal=Anti-Cancer Agents in Medicinal Chemistry |volume=10|issue=10|pages=753–768|doi=10.2174/187152010794728639|pmid=21269250|pmc=3267166}}</ref> This integrin is upregulated in tumor and activated endothelial cells.<ref name=":1">{{Cite journal|last1=Liu|first1=Jie|last2=Yuan|first2=Shuanghu|last3=Wang|first3=Linlin|last4=Sun|first4=Xindong|last5=Hu|first5=Xudong|last6=Meng|first6=Xue|last7=Yu|first7=Jinming|date=2019-01-10|title=Diagnostic and Predictive Value of Using RGD PET/CT in Patients with Cancer: A Systematic Review and Meta-Analysis|journal=BioMed Research International|language=en|volume=2019|pages=e8534761|doi=10.1155/2019/8534761|pmid=30733968|pmc=6348803|issn=2314-6133|doi-access=free}}</ref> This and other anti-[[Angiogenesis|angiogenic]] therapies depend on cutting off the blood supply to the tumor micro-environment, leading to [[Hypoxia (medical)|hypoxia]] and [[necrosis]].<ref>{{Cite journal|last1=Al-Abd|first1=Ahmed M.|last2=Alamoudi|first2=Abdulmohsin J.|last3=Abdel-Naim|first3=Ashraf B.|last4=Neamatallah|first4=Thikryat A.|last5=Ashour|first5=Osama M.|date=2017-11-01|title=Anti-angiogenic agents for the treatment of solid tumors: Potential pathways, therapy and current strategies – A review|journal=Journal of Advanced Research|language=en|volume=8|issue=6|pages=591–605|doi=10.1016/j.jare.2017.06.006|pmid=28808589|pmc=5544473|issn=2090-1232}}</ref> Cilengitide has been evaluated for the treatment of [[glioblastoma]], but, as is the case for other anti-angiogenic therapies, has not been shown to alter progression or improve survival either alone or in combination with standard treatments.<ref>{{Cite journal|title=Antiangiogenic therapy for high-grade glioma|journal = Cochrane Database of Systematic Reviews|issue = 9|last1=Khasraw|first1=Mustafa|last2=Ameratunga|first2=Malaka S|last3=Grant|first3=Robin|last4=Wheeler|first4=Helen|last5=Pavlakis|first5=Nick|date=2014-09-22|pages=CD008218|language=en|doi=10.1002/14651858.cd008218.pub3|pmid = 25242542}}</ref>

[[File:Integrin alphaVbeta3 and RGD Binding.png|thumb|Crystal structure of an extracellular segment of integrin alphaVbeta3 complexed with a cyclic peptide containing the arginyl-glycyl-aspartic acid (RGD) sequence. RGD is shown in maroon.|286x286px]]

CEND-1, also known as [[iRGD]], is a cyclic peptide that homes to tumors via binding to [[integrin alpha V]] receptors.<ref>{{Cite journal|last1=Dean|first1=A.|last2=Gill|first2=S.|last3=McGregor|first3=M.|last4=Broadbridge|first4=V.|last5=Jarvelainen|first5=H. A.|last6=Price|first6=T. J.|date=2020-09-01|title=1528P Phase I trial of the first-in-class agent CEND-1 in combination with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer|url=https://www.annalsofoncology.org/article/S0923-7534(20)42007-1/abstract|journal=Annals of Oncology|language=English|volume=31|pages=S941|doi=10.1016/j.annonc.2020.08.2011|s2cid=225179739|issn=0923-7534|doi-access=free}}</ref> It also binds and activates [[neuropilin-1]], leading to a temporary opening of the tumor and an enhanced delivery of anti-cancer agents into the tumor tissue. It is currently being tested in clinical trials in solid tumor patients.<ref>{{cite web|url=https://clinicaltrials.gov/ct2/show/NCT03517176|title = A Phase 1 Clinical Trial of CEND-1 in Combination with Nabpaclitaxel and Gemcitabine in Metastatic Exocrine Pancreatic Cancer|date = 24 October 2020}}</ref>

=== Diagnostics ===

As anti-angiogenic cancer therapies have achieved widespread use, there has been increased interest in non-invasive monitoring of angiogenesis. One of the most extensively examined targets of angiogenesis is integrin αVβ3. [[Radiolabeled]] peptides containing RGD show high affinity and selectivity for integrin αVβ3 and are being investigated as tools to monitor treatment response of tumors via [[Positron emission tomography|PET imaging]].<ref name=":16" /> These include ¹⁸F-Galacto-RGD, ¹⁸F-Fluciclatide-RGD, ¹⁸F-RGD-K5, ⁶⁸Ga-NOTA-RGD, ⁶⁸Ga-NOTA-PRGD2, ¹⁸F-Alfatide, ¹⁸F-Alfatide II, and ¹⁸F-FPPRGD2.<ref name=":1" /><ref name=":0" /><ref name=":16">{{Cite journal|last1=Chen|first1=Haojun|last2=Niu|first2=Gang|last3=Wu|first3=Hua|last4=Chen|first4=Xiaoyuan|date=2016-01-01|title=Clinical Application of Radiolabeled RGD Peptides for PET Imaging of Integrin αvβ3|journal=Theranostics|volume=6|issue=1|pages=78–92|doi=10.7150/thno.13242|issn=1838-7640|pmc=4679356|pmid=26722375}}</ref> In a meta-analysis of studies using PET/CT in patients with cancer, it was shown that this diagnostic method may be very useful for detecting malignancies and predicting short-term outcomes, although larger-scale studies are needed.<ref name=":1" />

== Use in bioengineering ==

RGD-based peptides have found many applications in biological research and medical devices. [[Culture plate]]s coated with peptides mimicking ECM proteins' adhesion motifs, which promote prolonged culture of human [[embryonic stem cell]]s, are on the market.<ref>{{Cite journal|last1=Villa-Diaz|first1=L. G.|last2=Ross|first2=A. M.|last3=Lahann|first3=J.|last4=Krebsbach|first4=P. H.|date=2013|title=Concise Review: The Evolution of human pluripotent stem cell culture: From feeder cells to synthetic coatings|journal=Stem Cells|language=en|volume=31|issue=1|pages=1–7|doi=10.1002/stem.1260|issn=1549-4918|pmc=3537180|pmid=23081828}}</ref> RGD is also a universally used tool in the construction of multifunctional [[Smart material|"smart" materials]], such as tumor-targeted nanoparticles.<ref>{{Cite journal|last=Ruoslahti|first=Erkki|date=2012-07-24|title=Peptides as Targeting Elements and Tissue Penetration Devices for Nanoparticles|journal=Advanced Materials|language=en|volume=24|issue=28|pages=3747–3756|doi=10.1002/adma.201200454|pmid=22550056|issn=1521-4095|pmc=3947925}}</ref> Further, RGD is widely used in tissue engineering to promote tissue regeneration.<ref name=":6" />

[[File:RGD-Modified Nanoparticle Binding to an Integrin.png|thumb|340x340px|Illustration of an RGD-modified, drug-loaded nanoparticle binding to an integrin on the cell surface.]]

=== Drug delivery ===

Conventional [[drug delivery]] methods, such as systemic or topical delivery, are associated with many issues such as low solubility, off-target effects, and disadvantageous [[pharmacokinetics]]. [[Nanoparticle]]s have been employed to increase solubility and target delivery of the drug to the desired tissue, increasing concentration of the drug at the site of action and decreasing drug concentration elsewhere, thereby increasing the efficacy of the drug and decreasing side effects.<ref>{{Cite journal|last1=Abasian|first1=Payam|last2=Ghanavati|first2=Sonya|last3=Rahebi|first3=Saeed|last4=Khorasani|first4=Saied Nouri|last5=Khalili|first5=Shahla|date=2020|title=Polymeric nanocarriers in targeted drug delivery systems: A review|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/pat.5031|journal=Polymers for Advanced Technologies|language=en|volume=31|issue=12|pages=2939–2954|doi=10.1002/pat.5031|s2cid=225495309|issn=1099-1581}}</ref><ref name=":6" /> RGD has been employed to target nanoparticles containing drugs to specific cell types, especially cancer cells expressing integrin αvβ3.<ref name=":6" />

Many research groups utilize RGD to target the chemotherapeutic [[doxorubicin]] to cancer cells. Like other chemotherapeutics of its class, doxorubicin causes hair loss, nausea, vomiting, and [[Bone marrow suppression|myelosuppression]], and can lead to [[cardiomyopathy]] and [[Heart failure|congestive heart failure]]. Clinically available Doxil utilizes liposomes to reduce accumulation of doxorubicin in myocardial tissue, thereby reducing cardiotoxicity.<ref name=":12">{{Cite journal|last1=Sun|first1=Yuan|last2=Kang|first2=Chen|last3=Liu|first3=Fei|last4=Zhou|first4=You|last5=Luo|first5=Lei|last6=Qiao|first6=Hongzhi|date=2017|title=RGD Peptide-Based Target Drug Delivery of Doxorubicin Nanomedicine|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ddr.21399|journal=Drug Development Research|language=en|volume=78|issue=6|pages=283–291|doi=10.1002/ddr.21399|pmid=28815721|s2cid=205750284|issn=1098-2299}}</ref> However, such nanoparticles rely on passive targeting of tumors by the [[Enhanced permeability and retention effect|EPR effect]], which varies by patient and tumor type.<ref name=":12" /><ref>{{Cite journal|last1=Shi|first1=Yang|last2=van der Meel|first2=Roy|last3=Chen|first3=Xiaoyuan|last4=Lammers|first4=Twan|date=2020|title=The EPR effect and beyond: Strategies to improve tumor targeting and cancer nanomedicine treatment efficacy|url=https://www.thno.org/v10p7921.htm|journal=Theranostics|language=en|volume=10|issue=17|pages=7921–7924|doi=10.7150/thno.49577|issn=1838-7640|pmc=7359085|pmid=32685029}}</ref> Active targeting strategies aim to increase drug transport into cells to improve efficacy and counter multidrug resistance.<ref name=":12" />

In addition to doxorubicin, RGD-conjugated nanomaterials have been used to deliver the chemotherapeutics [[cisplatin]], [[docetaxel]], [[paclitaxel]], [[5-Fluorouracil|5-fluorouracil]], and [[Gemcitabine]] to cancer cells. Such nanomaterials have also been used to deliver combination [[Cytotoxicity|cytotoxic]] and [[Vascular disrupting agent|vascular disrupting]] therapies.<ref name=":6" />

=== Gene delivery ===

While [[gene therapy]] has gained significant attention from the medical community, especially for cancer therapy, a lack of safe and efficient [[Vectors in gene therapy|gene delivery vectors]] has become a bottleneck to clinical translation.<ref name=":13" /> While [[viral vector]]s demonstrate high transfection efficiency and protect delivered genes, there are safety concerns associated with immune responses to the virus. Many nonviral vectors have been proposed, especially cationic [[lipid]]s and [[polymer]]s. However, these demonstrate low transfection efficiency compared to viruses. Therefore RGD has been coupled to nonviral vectors to target delivery of genetic material to the desired cells, thereby increasing [[transfection]] efficiency.<ref name=":13">{{Cite journal|last1=Park|first1=J.|last2=Singha|first2=K.|last3=Son|first3=S.|last4=Kim|first4=J.|last5=Namgung|first5=R.|last6=Yun|first6=C.-O.|author-link6= Chae Ok-Yun|last7=Kim|first7=W. J.|date=November 2012|title=A review of RGD-functionalized nonviral gene delivery vectors for cancer therapy|journal=Cancer Gene Therapy|language=en|volume=19|issue=11|pages=741–748|doi=10.1038/cgt.2012.64|pmid=23018622|s2cid=8809501|issn=1476-5500|doi-access=free}}</ref>

=== Tissue engineering ===

[[File:Gefäßprothese.JPG|thumb|273x273px|A tissue engineered vascular graft.]]

Tissue engineering aims to replace lost or damaged tissues within the body. The success of such efforts has depended greatly upon the ability to direct cell behavior and encourage regeneration of tissues. A key method of doing so utilizes ECM-derived [[Ligand (biochemistry)|ligands]] such as RGD to control cellular responses to a [[biomaterial]], such as attachment, proliferation, and differentiation.<ref name=":15" />

==== Vascular tissue ====

High rates of cardiovascular disease creates a high demand for grafts for vascular bypass surgery, especially small-diameter grafts which prevent [[Vascular occlusion|occlusion]].<ref name=":6">{{Cite journal|last1=Alipour|first1=Mohsen|last2=Baneshi|first2=Marzieh|last3=Hosseinkhani|first3=Saman|last4=Mahmoudi|first4=Reza|last5=Jabari Arabzadeh|first5=Ali|last6=Akrami|first6=Mohammad|last7=Mehrzad|first7=Jalil|last8=Bardania|first8=Hassan|date=April 2020|title=Recent progress in biomedical applications of RGD-based ligand: From precise cancer theranostics to biomaterial engineering: A systematic review|url=https://pubmed.ncbi.nlm.nih.gov/31854488/|journal=Journal of Biomedical Materials Research. Part A|volume=108|issue=4|pages=839–850|doi=10.1002/jbm.a.36862|issn=1552-4965|pmid=31854488|s2cid=209417891}}</ref> Modifying vascular tissue grafts with RGD has been shown to inhibit platelet adhesion, improve cell infiltration and enhance endothelialization.<ref name=":6" /> There have also been efforts to regenerate damaged heart tissues by applying cardiac patches following myocardial infarction.<ref>{{Cite journal|last1=Pomeroy|first1=Jordan E.|last2=Helfer|first2=Abbigail|last3=Bursac|first3=Nenad|date=2020-09-01|title=Biomaterializing the promise of cardiac tissue engineering|journal=Biotechnology Advances|language=en|volume=42|pages=107353|doi=10.1016/j.biotechadv.2019.02.009|pmid=30794878|pmc=6702110|issn=0734-9750}}</ref> The addition of RGD onto a cardiac tissue scaffold has been shown to promote cell adhesion, prevent [[apoptosis]] and enhance tissue regeneration.<ref>{{Cite journal|last1=Shachar|first1=Michal|last2=Tsur-Gang|first2=Orna|last3=Dvir|first3=Tal|last4=Leor|first4=Jonathan|last5=Cohen|first5=Smadar|date=2011-01-01|title=The effect of immobilized RGD peptide in alginate scaffolds on cardiac tissue engineering|url=https://www.sciencedirect.com/science/article/pii/S1742706110003545|journal=Acta Biomaterialia|language=en|volume=7|issue=1|pages=152–162|doi=10.1016/j.actbio.2010.07.034|pmid=20688198|issn=1742-7061}}</ref> RGD peptide has also been used to improve endothelial cell adhesion and [[Cell proliferation|proliferation]] on synthetic heart valves.<ref name=":7">{{Cite journal|last=Jana|first=Soumen|date=2019-11-01|title=Endothelialization of cardiovascular devices|url=https://www.sciencedirect.com/science/article/pii/S1742706119305987|journal=Acta Biomaterialia|language=en|volume=99|pages=53–71|doi=10.1016/j.actbio.2019.08.042|pmid=31454565|s2cid=201652737|issn=1742-7061}}</ref>

[[File:Hip joint replacement, United States, 1998 Wellcome L0060175.jpg|thumb|272x272px|A titanium alloy hip joint replacement.]]

==== Bone tissue ====

Bone defects or fractures can occur in a number of ways, including trauma, neoplasm, osteoporosis, or congenital disorders. Treatments such as autografts or allografts suffer from lack of donor sites and chance of communicable disease, respectively. There is therefore considerable interest in developing tissue engineered bone constructs, which should encourage tissue regeneration.<ref>{{Cite journal|last1=Venkatesan|first1=Jayachandran|last2=Bhatnagar|first2=Ira|last3=Manivasagan|first3=Panchanathan|last4=Kang|first4=Kyong-Hwa|last5=Kim|first5=Se-Kwon|date=2015-01-01|title=Alginate composites for bone tissue engineering: A review|url=https://www.sciencedirect.com/science/article/pii/S0141813014004735|journal=International Journal of Biological Macromolecules|language=en|volume=72|pages=269–281|doi=10.1016/j.ijbiomac.2014.07.008|pmid=25020082|issn=0141-8130}}</ref> Coating an implant with RGD has been shown to improve bone cell adhesion, proliferation and survival. ''In vivo'' studies of such coatings additionally demonstrated improved [[osseointegration]]. Modifying a titanium implant surface with a protein containing RGD improved bone mineralization and implant integration and prevented failure of the prosthetic.<ref name=":7" />

==== Eye tissue ====

Damage to the cornea causes significant vision impairment, the most common treatment for which is allograft cornea transplantation. However, donor corneal grafts are in short supply and, like other tissue grafts, carry the risk of rejection or communicable disease.<ref name=":18" /> Thus, tissue engineered options are desirable. In silk biomaterial scaffolds which replicate the hierarchical structure of the [[cornea]], the addition of RGD improved cell attachment, alignment, proliferation, and ECM [[Protein expression (biotechnology)|protein expression]].<ref name=":6" /><ref name=":18">{{Cite journal|last1=Gil|first1=Eun Seok|last2=Mandal|first2=Biman B.|last3=Park|first3=Sang-Hyug|last4=Marchant|first4=Jeffrey K.|last5=Omenetto|first5=Fiorenzo G.|last6=Kaplan|first6=David L.|author6-link=David L. Kaplan (engineer)|date=2010-12-01|title=Helicoidal multi-lamellar features of RGD-functionalized silk biomaterials for corneal tissue engineering|journal=Biomaterials|language=en|volume=31|issue=34|pages=8953–8963|doi=10.1016/j.biomaterials.2010.08.017|pmid=20801503|pmc=2949540|issn=0142-9612}}</ref> Additionally, RGD has been used in regeneration of retinal pigmented epithelium. This tissue can be generated from human embryonic and [[induced pluripotent stem cell]]s, however with inefficient [[Cellular differentiation|differentiation]]. It has been shown that RGD-[[Alginic acid|alginate]] [[hydrogel]]s improve derivation of retinal tissue from stem cells.<ref name=":6" /><ref>{{Cite journal|last1=Hunt|first1=Nicola C.|last2=Hallam|first2=Dean|last3=Karimi|first3=Ayesha|last4=Mellough|first4=Carla B.|last5=Chen|first5=Jinju|last6=Steel|first6=David H. W.|last7=Lako|first7=Majlinda|date=2017-02-01|title=3D culture of human pluripotent stem cells in RGD-alginate hydrogel improves retinal tissue development|journal=Acta Biomaterialia|language=en|volume=49|pages=329–343|doi=10.1016/j.actbio.2016.11.016|pmid=27826002|issn=1742-7061|doi-access=free}}</ref>

[[File:Cell on 2D Monolayer vs. 3D Hydrogel with RGD.png|thumb|488x488px|A cell on a 2D monolayer (left) and cells in a 3D hydrogel (right). Red bars represent RGD peptide.]]

==== Ligand presentation ====

[[File:Global density vs. local density.png|thumb|371x371px|Global (left) and local (right) density. Local density of RGD peptides in a cell scaffold occurs on the micro/nano scales Red dots represent RGD peptide.]]

RGD and other bioactive ligands can be presented on the surface of a biomaterial in a number of different spatial arrangements, and it has been demonstrated that these arrangements have a significant impact on cell behavior. In [[self-assembled monolayer]]s, it was found that adhesion and proliferation of both [[human umbilical vein endothelial cell]]s (HUVECs) and human [[mesenchymal stem cell]]s (MSCs) increased as a function of RGD peptide density. These studies also showed that RGD density could change integrin expression, which has been postulated to enable control of biochemical signaling pathways. Further investigation of MSCs on self-assembled monolayers showed that modulating RGD density and the affinity of RGD for αvβ3 (through use of linear and [[Cyclic compound|cyclized]] RGD) could be used to control the [[Cellular differentiation|differentiation]] of MSCs.<ref name=":17">{{Cite journal|last1=Satav|first1=Tushar|last2=Huskens|first2=Jurriaan|last3=Jonkheijm|first3=Pascal|date=2015|title=Effects of Variations in Ligand Density on Cell Signaling|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/smll.201500747|journal=Small|language=en|volume=11|issue=39|pages=5184–5199|doi=10.1002/smll.201500747|pmid=26292200|issn=1613-6829}}</ref> The effect of RGD presentation on cells in 3D biomaterials, which more accurately replicate the ''in vivo'' environment, has also been evaluated. In degradable [[polyethylene glycol]] hydrogels, the length of capillary-like structures formed by HUVECs was directly proportional to the density of RGD in the hydrogel.<ref name=":17" /><ref>{{Cite journal|last1=Nguyen|first1=Eric H.|last2=Zanotelli|first2=Matthew R.|last3=Schwartz|first3=Michael P.|last4=Murphy|first4=William L.|date=2014-02-01|title=Differential effects of cell adhesion, modulus and VEGFR-2 inhibition on capillary network formation in synthetic hydrogel arrays|journal=Biomaterials|language=en|volume=35|issue=7|pages=2149–2161|doi=10.1016/j.biomaterials.2013.11.054|pmid=24332391|pmc=3970236|issn=0142-9612}}</ref> Additionally, studies in [[Nano-pattering|nano-patterning]] have shown that, whereas an increase in global RGD density increases cell adhesion strength until saturation, an increase in local (mico/nano-scale) RGD density does not follow this trend.<ref name=":17" />

== Alternatives ==

RGD is the most widely used of a larger class of cell adhesive peptides. These short amino acid sequences are the minimum motif of a larger protein that is necessary for binding to a cell surface receptor that drives cell adhesion.<ref name=":8">{{Cite journal|last1=Huettner|first1=Nick|last2=Dargaville|first2=Tim R.|last3=Forget|first3=Aurelien|date=2018-04-01|title=Discovering Cell-Adhesion Peptides in Tissue Engineering: Beyond RGD|url=https://www.sciencedirect.com/science/article/pii/S0167779918300295|journal=Trends in Biotechnology|language=en|volume=36|issue=4|pages=372–383|doi=10.1016/j.tibtech.2018.01.008|pmid=29422411|issn=0167-7799|doi-access=free}}</ref> The majority (89%) of published studies on biomaterials functionalized with cell adhesive peptides use RGD, whereas [[IKVAV motif|IKVAV]] and YIGSR are used in 6%, and 4% of those studies, respectively.<ref name=":8" /> Cell adhesive peptides isolated from fibronectin include RGD, RGDS, PHSRN, and REDV.<ref name=":4">{{Cite journal|last=Hamley|first=I. W.|date=2017-12-11|title=Small Bioactive Peptides for Biomaterials Design and Therapeutics|url=https://pubs.acs.org/doi/pdf/10.1021/acs.chemrev.7b00522|journal=Chemical Reviews|volume=117|issue=24|pages=14015–14041|doi=10.1021/acs.chemrev.7b00522|pmid=29227635|issn=0009-2665}}</ref><ref>{{Cite journal|last1=Kakinoki|first1=Sachiro|last2=Yamaoka|first2=Tetsuji|date=2015-04-15|title=Single-Step Immobilization of Cell Adhesive Peptides on a Variety of Biomaterial Substrates via Tyrosine Oxidation with Copper Catalyst and Hydrogen Peroxide|url=https://doi.org/10.1021/acs.bioconjchem.5b00032|journal=Bioconjugate Chemistry|volume=26|issue=4|pages=639–644|doi=10.1021/acs.bioconjchem.5b00032|pmid=25742028|issn=1043-1802}}</ref> YIGSR and IKVAV are isolated from laminin, whereas DGEA and GFOGER/GFPGER are isolated from collagen.<ref name=":4" /> Artificial amino acid sequences, which bear no biological similarity to ECM proteins, have also been synthesized, and include the α5β1-specific peptide RRETAWA.<ref name=":15">{{Cite journal|last1=Dhavalikar|first1=Prachi|last2=Robinson|first2=Andrew|last3=Lan|first3=Ziyang|last4=Jenkins|first4=Dana|last5=Chwatko|first5=Malgorzata|last6=Salhadar|first6=Karim|last7=Jose|first7=Anupriya|last8=Kar|first8=Ronit|last9=Shoga|first9=Erik|last10=Kannapiran|first10=Aparajith|last11=Cosgriff-Hernandez|first11=Elizabeth|date=2020|title=Review of Integrin-Targeting Biomaterials in Tissue Engineering|journal=Advanced Healthcare Materials|language=en|volume=9|issue=23|pages=2000795|doi=10.1002/adhm.202000795|issn=2192-2659|pmc=7960574|pmid=32940020}}</ref><ref name=":9">{{Cite journal|last1=Meyers|first1=Steven R.|last2=Grinstaff|first2=Mark W.|date=2011-10-18|title=Biocompatible and Bioactive Surface Modifications for Prolonged In Vivo Efficacy|journal=Chemical Reviews|volume=112|issue=3|pages=1615–1632|doi=10.1021/cr2000916|issn=0009-2665|pmc=3878818|pmid=22007787}}</ref>

{| class="wikitable"

|+Selected Cell Adhesive Peptides

!Peptide

!Source

!Receptor Integrin

!Major uses

!References

|-

|RGD(S)

|Fibronectin

|α3β1, α5β1, α8β1, αvβ1, αvβ3, αvβ5, αvβ6, αIIbβ3

|Promotes cell adhesion, targets tumors, used for drug discovery

|,<ref name=":14" /><ref name=":11" /><ref name=":6" /><ref name=":4" />

|-

|PHSRN

|Fibronectin

|α5β1

|Synergistic for cell adhesion when covalently attached to RGD

|,<ref name=":15" /><ref name=":4" />

|-

|REDV

|Fibronectin

|α4β1

|Promotes endothelial cell adhesion

|,<ref name=":8" /><ref name=":4" />

|-

|YIGSR

|Laminin

|α4β1

|Promotes cell adhesion, inhibits angiogenesis and tumor growth

|,<ref name=":8" /><ref name=":4" />

|-

|IKVAV

|Laminin

|α3β1

|Promotes cell adhesion and neurite outgrowth

|,<ref name=":8" /><ref name=":4" />

|-

|DGEA

|Collagen type I

|α2β1

|Inhibits adhesion of platelets or adenocarcinoma to collagen

|,<ref name=":8" /><ref name=":4" />

|-

|GFOGER/GFPGER

|Collagen type I

|α1β1 and α2β1

|Promotes osteogenesis in biomaterials

|,<ref name=":14" /><ref name=":8" /><ref name=":4" />

|-

|Eptifibatide

|Derived from snake venom

|[[Glycoprotein IIb/IIIa|αIIbβ3]]

|Thrombosis inhibition

|<ref name=":10">{{Cite journal|last1=Phillips|first1=David R|last2=Scarborough|first2=Robert M|date=1997-08-18|title=Clinical Pharmacology of Eptifibatide|url=https://www.sciencedirect.com/science/article/pii/S0002914997005729|journal=The American Journal of Cardiology|language=en|volume=80|issue=4, Supplement 1|pages=11B–20B|doi=10.1016/S0002-9149(97)00572-9|pmid=9291241|issn=0002-9149}}</ref>

|-

|RRETAWA

|Synthetic

|α5β1

|Promotes endothelial cell adhesion without platelet adhesion

|,<ref name=":15" /><ref name=":9" />

|}

== Chemical modifications ==

Linear RGD peptides suffer from low binding affinity, rapid degradation by proteases, and lack of specificity for integrin type.<ref name=":5">{{Cite journal|last1=Shi|first1=Jiyun|last2=Wang|first2=Fan|last3=Liu|first3=Shuang|date=2016-02-01|title=Radiolabeled cyclic RGD peptides as radiotracers for tumor imaging|url=https://doi.org/10.1007/s41048-016-0021-8|journal=Biophysics Reports|language=en|volume=2|issue=1|pages=1–20|doi=10.1007/s41048-016-0021-8|issn=2364-3420|pmc=5071373|pmid=27819026}}</ref> RGD can be cyclized, or made into a [[cyclic compound]], via disulfide, thioether, or rigid aromatic ring linkers. This leads to an increase in binding affinity and selectivity for integrin αVβ3 relative to αIIBβ3.<ref name=":5" /><ref name=":13" /> For example, the cyclic peptide ACDCRGDCFCG, also known as RGD4C, was shown to be 200-fold more potent than commonly used linear RGD peptides.<ref name=":13" /> The structural rigidity of cyclic RGD peptides improves their binding properties and prevents degradation at the highly susceptible aspartic acid residue, thereby increasing their stability.<ref name=":13" /> Many RGD derivative drugs and diagnostics are cyclized, including Eptifibatide, Cilengitide, CEND-1, and ¹⁸F-Galacto-RGD, and ¹⁸F-Fluciclatide-RGD.<ref name=":2" /><ref name=":3" />

==References==

{{reflist}}

[[Category:Tripeptides]]