Anti-HIV Activity and Conformational Studies of Peptides Derived from the C-Terminal Sequence of SDF-1

Dettin, Monica; Pasquato, Antonella; Scarinci, C; Zanchetta, Marisa; Rossi, Anita De; Bello, Carlo Di

doi:10.1021/jm031067a

Cited by 18 publications

(11 citation statements)

References 25 publications

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“…CXCL12 has two major isoforms, α and β [16]. Both are derived from a single gene, while CXCL12β differs by an additional four amino acids (RLKM) at the C-terminal end due to alternative splicing [17]. CXCL12α is the predominant isoform secreted by marrow stromal cells and endothelial cells and is found in nearly all organs.…”

Section: Cxcl12 Cxcr4 and Cxcr7mentioning

confidence: 99%

CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression

Sun

Cheng

Hao

et al. 2010

Cancer Metastasis Rev

651

600

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Chemokines, small pro-inflammatory chemoattractant cytokines that bind to specific G-protein coupled seven-span transmembrane receptors (GPCRs), are major regulators of cell trafficking and adhesion. The chemokine CXCL12 [also called stromal-derived factor-1 (SDF-1)] is an important α-chemokine that binds primarily to its cognate receptor CXCR4 and thus regulates the trafficking of normal and malignant cells. For many years it was believed that CXCR4 was the only receptor for CXCL12. Yet recent work has demonstrated that CXCL12 also binds to another seven-transmembrane span receptor called CXCR7. Our group and others have established critical roles for CXCR4 and CXCR7 on mediating tumor metastasis in several types of cancers, in addition to their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Here we review the current concepts regarding the role of CXCL12/CXCR4/CXCR7 axis activation, which regulates the pattern of tumor growth and metastatic spread to organs expressing high levels of CXCL12 to develop secondary tumors. We also summarize recent therapeutic approaches to target these receptors and/or their ligands.

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Section: Cxcl12 Cxcr4 and Cxcr7mentioning

confidence: 99%

CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression

Sun

Cheng

Hao

et al. 2010

Cancer Metastasis Rev

651

600

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“…22 While the N-terminal sequence of SDF-1 is required for receptor binding, the C-terminal sequence of SDF-1 may affect the binding affinity to the CXCR4 receptor. 51 The absence of the C-terminal lysine in SDF-1 (1-67) may explain its reduced ability to inhibit HIV-1 replication, as we have already shown that SDF-1 (1-67) has reduced binding affinity to heparin/ heparin sulfate glycosaminoglycans as compared with SDF-1 (1-68). 25 In addition to being cleaved at the C-terminus by CPN, SDF-1␣ is cleaved at the N-terminus by a number of different enzymes to generate an inactive chemokine that can no longer activate the CXCR4 receptor, including CD26/dipeptidyl peptidase, 22,26 MMPs, 29 neutrophil elastase, 28 and cathepsin G. 27 The C-terminal loss of lysine is very rapid as compared with a much slower removal of the N-terminal amino acids lysine and proline.…”

Section: Discussionmentioning

confidence: 97%

Identification of carboxypeptidase N as an enzyme responsible for C-terminal cleavage of stromal cell-derived factor-1α in the circulation

Davis

Singer

Sierra

et al. 2005

Blood

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The chemokine stromal-derived factor-1␣ (SDF-1␣) is an essential regulator of hematopoiesis, lymphocyte homing, pre-Bcell growth, and angiogenesis. As SDF-1␣ is constitutively expressed in many tissues, chemokine function is mostly regulated by proteolytic degradation. Human serum cleaves the 68-amino acid chemokine, SDF-1␣, at both termini. The enzyme or enzymes responsible for the removal of the carboxy-terminal lysine from SDF-1␣, leading to significant reduction in biologic activity, have not been identified.Using a new biochemical assay for measuring the carboxy-terminal cleavage activity, we purified from serum and plasma a peptidase that specifically removes the carboxy-terminal lysine from SDF-1␣ and identified it as carboxypeptidase N (CPN, also known as kininase I, arginine carboxypeptidase, and anaphylotoxin inactivator). We demonstrate that SDF-1␣ in serum and plasma lacks the carboxy terminal lysine, and depletion of CPN from serum and plasma significantly reduces the SDF-1␣ carboxypeptidase activity. Purified CPN effectively and specifically removes the carboxy-terminal lysine from SDF-1␣ and significantly reduces the chemokine's biologic activity as a pre-B-cell growth factor and chemoattractant. Thus, in addition to its role as a regulator of the biologic activity of kinins and anaphylatoxins, CPN is an important regulator of the biologic activity of SDF-1␣ by reducing the chemokine-specific activity. IntroductionThe chemokine stromal-derived factor-1 (SDF-1) and its unique receptor, CXCR4, are key regulators of the hematopoietic, nervous, and cardiovascular systems during embryogenesis. 1-3 Knock-out mice for SDF-1 or CXCR4 die perinatally with a similar phenotype, including defects in the formation of the cerebellum, the ventricular septum of the heart, the vasculature of the gastrointestinal system, and the lympho-hematopoietic system. [4][5][6][7] After birth, SDF-1 and CXCR4 continue to play key roles in regulating physiologic hematopoiesis and angiogenesis. [8][9][10][11][12][13][14][15] Studies in vitro have shown that SDF-1 functions as a growth factor for immature B lymphocytes and promotes chemotaxis in CXCR4-expressing cells, including tumor cells. 1,3,9,[16][17][18] Since CXCR4 can function as a coreceptor for T-cell tropic HIV-1, SDF-1 and CXCR4 may also affect the course of HIV-1 infection. 19,20 SDF-1␣ is a highly conserved chemokine in evolution, only a single conservative substitution (I to V) distinguishes the human chemokine from the mouse chemokine. 21,22 Two forms of SDF-1 are generated, ␣ and ␤, which are identical in amino acid sequence except for the presence of 4 additional amino acids at the carboxy terminus of SDF-1␤. 21,22 A third form of SDF-1 was identified in rat, SDF-1␥, which is predicted to code for a protein identical to SDF-1␤, except for the insertion of 30 additional amino acids at the carboxy terminus. 23 Structure-function studies have identified the amino terminal region of SDF-1 as critical to CXCR4 receptor activation. 22,24 SDF-1 lacking the amino term...

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“…The antibody may recognize an epitope in the C-terminal of SDF-1a, because it did not cross-react with SDF-1b [15]. The difference between SDF-1a (68 residues) and SDF-1b (72 residues) lies in the additional four C-terminal amino acids in the SDF-1b sequence [16].…”

Section: Discussionmentioning

confidence: 99%

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, increases the number of circulating CD34+CXCR4+ cells in patients with type 2 diabetes

et al. 2015

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We investigated the effects of sitagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, on the number of circulating CD34(+)CXCR4(+)cells, a candidate for endothelial progenitor cells (EPCs), plasma levels of stromal cell-derived factor (SDF)-1α, a ligand for CXCR4 receptor and a substrate for DPP-4, and plasma levels of interferon-inducible protein (IP)-10, for a substrate for DPP-4, in patients with type 2 diabetes. We studied 30 consecutive patients with type 2 diabetes who had poor glycemic control despite treatment with metformin and/or sulfonylurea. Thirty diabetic patients were randomized in a 2:1 ratio into a sitagliptin (50 mg/day) treatment group or an active placebo group (glimepiride 1 mg/day) for 12 weeks. Both groups showed similar improvements in glycemic control. The number of circulating CD34(+)CXCR4(+) cells was increased from 30.5 (20.0, 47.0)/10(6) cells at baseline to 55.5 (31.5, 80.5)/10(6) cells at 12 weeks of treatment with 50 mg/day sitagliptin (P = 0.0014), while showing no significant changes in patients treated with glimepiride. Plasma levels of SDF-1α and IP-10, both physiological substrates of endogenous DPP-4 and chemokines, were significantly decreased at 12 weeks of sitagliptin treatment. In conclusion, treatment with sitagliptin increased the number of circulating CD34(+)CXCR4(+) cells by approximately 2-fold in patients with type 2 diabetes.

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Anti-HIV Activity and Conformational Studies of Peptides Derived from the C-Terminal Sequence of SDF-1

Cited by 18 publications

References 25 publications

CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression

CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression

Identification of carboxypeptidase N as an enzyme responsible for C-terminal cleavage of stromal cell-derived factor-1α in the circulation

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, increases the number of circulating CD34+CXCR4+ cells in patients with type 2 diabetes

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