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PubMed1992

Evidence that autologous idiotypic regulation of anti-arginine-glycine-aspartic acid autoantibodies may influence development and progression of syphilitic lesions in infected rabbits.

The 83-kDa receptor protein of Treponema pallidum (TpN83) recognizes and binds fibronectin (Fn) at the amino acid sequence RGD site. By using experimentally infected animals, we have demonstrated that immunoglobulin G antibodies to this antigen and autoantibodies to the RGD site of Fn are putative components of immune complexes. This, and other findings, led us to initially hypothesize that anti-idiotypes (anti-Id) of an anti-TpN83 response are autoantibodies to RGD. Alternatively, we reasoned that if anti-Fn autoantibodies played a role in the pathogenesis of syphilis, then down-regulation of such a response by the Id network might directly affect progression of the disease. To test the hypothesis, rabbits were immunized with either affinity-purified TpN83 antigen or the synthetic Fn-7 peptide, KYGRGDS, and subsequently challenged with T. pallidum. Compared with results obtained with unimmunized, control rabbits, accelerated lesion development was noted in the rabbits immunized with TpN83. Pronounced, though unexpected, differences with respect to lesion development and progression were noted in the animals immunized with Fn-7 and then challenged intravenously; a minimal number of lesions appeared with a delayed onset. These lesions, like the localized chancres seen following intradermal challenge, were smaller and minimally ulcerated, and they healed rapidly. The Fn-7-immunized rabbits all differed from the controls in that anti-Id to anti-RGD F(ab')2 were demonstrable within 4 weeks following infection; decreases in anti-Fn autoantibody levels were associated with concomitant increases in anti-Id levels. Immunoglobulin Gs (anti-Id) from these animals following elution from anti-RGD F(ab')2 immunoaffinity columns also reacted with affinity-purified TpN83 antigen in immunoassays. These results suggest that down-regulation of autoreactive clones by manipulation of the idiotypic network in experimental syphilis warrants further investigation.

Amino Acid Sequence↗
PubMed1990

Arginine-glycine-aspartic acid- and fibrinogen gamma-chain carboxyterminal peptides inhibit platelet adherence to arterial subendothelium at high wall shear rates. An effect dissociable from interference with adhesive protein binding.

Arg-Gly-Asp (RGD)- and fibrinogen gamma-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein IIb-IIIa complex (GP IIb-IIIa). GP IIb-IIIa, vWF, and Fn are essential for normal platelet adherence to subendothelium. We added peptides to normal citrated whole blood before perfusion over human umbilical artery subendothelium and evaluated platelet adherence morphometrically at high (2,600 s-1) and low (800 s-1) wall shear rates. We also examined the effects of the peptides on platelet adhesion to collagen in a static system. At the high wall shear rate, RGDS and GQQHHLGGAKQAGDV caused dose-dependent reduction in the surface coverage with spread and adherent platelets. Amino acid transposition and conservative substitutions of RGD peptides and the AGDV peptide significantly inhibited platelet adherence at 2,600 s-1. By contrast, the modified RGD peptides and AGDV do not affect adhesive protein binding to platelets. None of the native or modified RGD- or fibrinogen gamma-chain peptides significantly inhibited either platelet adherence to subendothelium at 800 s-1 or platelet adhesion to collagen. Our findings demonstrate that peptides that interfere with adhesive protein binding to GP IIb-IIIa inhibit platelet adherence to vascular subendothelium with flowing blood only at high wall shear rates. Platelet adherence to subendothelium at high wall shear rates appears to be mediated by different recognition specificities from those required for fluid-phase adhesive protein binding or static platelet adhesion.

Amino Acid Sequence↗
PubMed1989

Tarantula (Eurypelma californicum) venom, a multicomponent system.

The venom of the tarantula Eurypelma californicum was analysed biochemically, the components were isolated and characterized. The pH value of the crude venom is 5.3 +/- 0.3. After dilution with distilled water, UV-absorption spectra showed a single maximum at 258 nm (pH ca. 7.0). A second maximum at 328 nm emerged above pH 8.0. Protein concentration of the venom is ca. 65 mg/ml. After Coomassie staining SDS-PAGE patterns show three major bands with apparent molecular masses around 40 kDa, 4.3 kDa and 1.3 kDa besides some weak high molecular protein bands. The following low-molecular mass constituents were determined in the crude venom: ATP, ADP, AMP, glutamic acid, aspartic acid, gamma-aminobutyric acid, glucose and the ions potassium, sodium, calcium, magnesium and chloride; the osmolality was 361 micro0smol/ml. The LD50 value for female cockroaches was 0.15 microliters venom per g body weight and for male cockroaches 0.4 microliters venom per g body weight. Separation of the crude venom by gel chromatography yielded four elution peaks. Peak I contains the enzyme hyaluronidase. The activity is 200-900 U/microliters. Peak II contains a mixture of toxic peptides. Peak III contains the 1.3-kDa components of SDS-PAGE and peak IV mainly contains ATP. Venom proteins including the enzyme hyaluronidase were precipitated by 5% trichloroacetic acid. The supernatant was separated by HPLC into 13 fractions. Fraction 1 contains glutamic acid, aspartic acid, gamma-aminobutyric acid and ATP; fraction 2 contains ATP, ADP and AMP as well as a component 2' visible in SDS-PAGE as 1.3-kDa band and consisting of spermine and tryptophan; fraction 3 contains ATP and an unknown component 3'; fractions 4-6 also show a 1.3-kDa band in SDS-PAGE, fraction 4 being tyrosylspermine and fractions 5 and 6 containing compounds of spermine and aromatic molecules; fraction 7 contains a peptide which lacks aromatic amino acids, it was sequenced from the N-terminus; fractions 8-13 contain very similar toxic peptides. The peptides in fractions 11 and 12, labeled ESTX for Eurypelma spider toxin, were cleaved with different enzymes and sequenced. They differ in one amino acid in position 26. Homologies with scorpion toxins and with a toxin of the spider Segestria florentina were found.

Adenosine Triphosphate↗
PubMed1986

Hemoglobin Woodville: alpha (2)6(A4) aspartic acid----tyrosine.

Hemoglobin Woodville was detected in a Vietnamese woman during antenatal and cord blood screening programs for families of South East Asian origin. The variant constitutes 9% of total hemoglobin and structural analysis demonstrated the substitution alpha 6 Asp----Tyr. Hematological data on the proposita were normal. No apparent clinical or pathological findings were associated with this abnormal hemoglobin.

Adult↗
PubMed2002

Arginine-glycine-aspartic acid (RGD)-peptide binds to both tumor and tumor-endothelial cells in vivo.

Targeting tumor cells or tumor vasculature by peptides is a promising strategy for delivering cytotoxic drugs for cancer therapy. The identification of efficient targeting peptides depends on the availability of informative methods for determining cellular binding specificities. Here, we have used fluorescence-activated cell-sorting (FACS) analysis in combination with an isopentane freezing method to show targeted binding of the Arg-Gly-Asp (RGD)-4C-peptide labeled with FITC, not only to endothelial cells but also to tumor cells in human breast cancer xenografts grown in nude mice. Nontumorous cells showed only background binding. This study suggests, that the RGD-4C-peptide can target tumor endothelial cells as well as tumor cells. Consequently, it should be possible to design a combination therapy approach against both targets.

Animals↗
PubMed2006

Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro.

The Arg-Gly-Asp (RGD) sequence was selected by using phage-display peptides to target tumors, focusing on targeting alpha(v) integrins in tumor blood vessels. Recent studies suggest that peptides containing the RGD sequence can bind to tumor cells, as well as tumor endothelial cells. To investigate whether the RGD peptide has other effects on tumor cells expressing alpha(v) integrins, besides its tumor targeting capability, we designed and synthesized a 10-amino peptide that contained the RGD sequence in a cyclic conformation with a disulfide bond, which specifically bound to breast cancer cell lines MDA-MB-231 and MCF-7. We found that this RGD peptide, GCGGRGDGGC, inhibited tumor cell proliferation in a dose-dependent manner, and also induced apoptosis and G1-phase cell cycle arrest in both of the cell lines that bound and internalized the peptide. Normal ovarian epithelial cells, which did not bind the RGD peptide, were unaffected. RGD peptide treatment also reduced cell invasiveness in both cell lines in vitro. This study suggests that the RGD peptide not only possesses tumor targeting capacity, but also has direct tumor cytotoxic and invasiveness inhibition effects dependent on the blockage of alpha(v) integrin activity, which would make it more efficient in tumor targeting therapy.

Antineoplastic Agents↗
PubMed1991

Arginine-glycine-aspartic acid binding leading to molecular stabilization between integrin alpha v beta 3 and its ligand.

Cell adhesion is characterized by an integrin-mediated ligand binding event followed by reorganization of the actin-cytoskeleton leading to cell spreading and/or migration. In this report we examine the role of integrin alpha v beta 3 in mediating cell attachment to vitronectin or a RGD-containing peptide in the presence of cytochalasin B to prevent actin polymerization. Under these conditions cell attachment to a RGD-containing peptide can be dissociated by excess soluble ligand whereas cells attached to vitronectin cannot. These results suggest that alpha v beta 3-mediated cell attachment to vitronectin results in a highly stabilized interaction that is independent of the actin-cytoskeleton. To investigate the molecular nature of this interaction alpha v beta 3 was purified to homogeneity, and its binding properties toward various ligands were measured in a solid-phase receptor assay. The data indicate that alpha v beta 3 binds to vitronectin or fibronectin in a nondissociable manner whereas a RGD-containing peptide derived from vitronectin binds specifically but is completely dissociable with a Kd of 9.4 x 10(-7) M. Moreover, chemical modification of alpha v beta 3 with limited glutaraldehyde treatment allowed vitronectin to bind in a RGD-dependent and dissociable manner, suggesting that receptor conformational changes or specific amino acid residues proximal to the ligand binding site(s) are involved in the stabilization event. Thus, in the absence of cytoskeletal proteins or other cellular components, integrin alpha v beta 3-ligand binding involves recognition of the RGD sequence leading to a highly stabilized protein-protein association.

Amino Acid Sequence↗
PubMed1990

Protection against gentamicin-induced early renal alterations (phospholipidosis and increased DNA synthesis) by coadministration of poly-L-aspartic acid.

Coadministration of polyaspartic acid protects against functional and pathological signs of gentamicin-induced nephrotoxicity in rats without reduction of drug accumulation in renal cortex (Williams et al., J. Pharmacol. Exp. Ther. 237: 919-925, 1986; Gilbert et al., J. Infect. Dis. 159: 945-953, 1989). We have assessed the influence of polyaspartic acid on the early alterations induced in kidney cortex by gentamicin, namely the lysosomal phospholipidosis and the increase in cell turnover. We used an infused rat model in which animals received a total dose of 100 mg/kg of gentamicin over 12 hr. Renal cortex was examined 2 hr (day 0) and 48 hr (day 2) after treatment. All animals received an injection of [3H]thymidine (200 microCi i.p.) before sacrifice. Coadministration of polyaspartic acid (drug-polypeptide mass ratio 1:2.5) did not modify the drug serum levels, as recorded during or shortly after the infusion. Yet, it was associated with 1) an increased (approximately 35%) drug cortical content at day 0; 2) a significant protection against both biochemical (decrease of sphingomyelinase activity at day 0; increase of lipid phosphorus content at day 2) and morphological (enlargement of lysosomes and deposition of myeloid bodies at day 2) signs of lysosomal phospholipidosis in proximal tubular cells; and 3) an almost complete protection against increased cell turnover (mostly in proximal tubules) in cortex at day 2, as assessed by the measurement of [3H]thymidine incorporation into DNA and the enumeration of S-phase cells after histoautoradiography. In addition, morphological studies revealed a larger number of apical vacuoles in proximal tubular cells of animals receiving polyaspartic acid alone (but not in combination with gentamicin), and the deposition of osmiophilic, homogenous material in the lysosomes of animals receiving the combination of gentamicin and polyaspartic acid. Together with the results reported in two companion papers (Kishore et al., J. Pharmacol. Exp. Ther. 867-874, and 875-885, 1990), these results provide evidence that protection afforded by polyaspartic acid extends to the earliest cellular alterations described in kidney for gentamicin, namely the lysosomal phospholipidosis, suggesting that this protecting agent exerts blocking effect from this step in the cascade of events relating drug cortical accumulation to renal toxicity.

Animals↗
PubMed1990

Binding of the snake venom-derived proteins applaggin and echistatin to the arginine-glycine-aspartic acid recognition site(s) on platelet glycoprotein IIb.IIIa complex inhibits receptor function.

In the present report we describe the platelet-binding characteristics of applaggin and echistatin, potent inhibitors of fibrinogen-dependent platelet aggregation derived from Agkistrodon piscivorus piscivorus and Echis carinatus snake venoms, respectively. Both molecules bound to unstimulated platelets in a specific and saturable manner. At saturation there were 37,100 +/- 3,150 (mean, +/- S.D.) molecules of applaggin and 27,200 +/- 2,816 molecules of echistatin bound/platelet, with dissociation constants (Kd) of 1.4 +/- 0.6 x 10(-7) M and 4.9 +/- 1.2 x 10(-7) M, respectively. Stimulation of platelets with ADP (10 microM) + epinephrine (2 microM) resulted in an increase in the number of molecules bound at saturation to 42,300 +/- 2,105 for applaggin and 32,185 +/- 3,180 for echistatin, with a Kd of 5.6 +/- 0.3 x 10(-8) M and 1.8 +/- 0.6 x 10(-7) M, respectively. The synthetic peptide (Arg)8-Gly-Asp-Val was a competitive antagonist of applaggin and echistatin binding to unstimulated platelets (Ki = 25 and 36 microM, respectively). Applaggin and echistatin inhibited the binding of fibrinogen to stimulated platelets in a dose-dependent manner, with an IC50 of 9 and 25 nM, respectively. In concert with inhibition of platelet aggregation, applaggin and echistatin inhibited platelet secretion and synthesis of thromboxane A2 induced by ADP, collagen, and human gamma-thrombin. The monclonal antibody, LJ-CP3, which inhibits the binding of Arg-Gly-Asp containing ligands to platelet GPIIb.IIIa, also inhibited applaggin binding to unstimulated platelets in a competitive manner (Ki = 4.5 microM). Thus, applaggin and echistatin bind to the platelet GPIIb.IIIa complex, and the Arg-Gly-Asp sequence plays a central role in mediating this interaction.

Adenosine Diphosphate↗
PubMed1987

Arginyl-glycyl-aspartic acid sequences and fibrinogen binding to platelets.

Human fibrinogen has an Arg-Gly-Asp-Ser (RGDS) sequence at residues 572-575 of its A alpha-chain. Although RGDS-containing peptides inhibit fibrinogen binding to stimulated platelets, these peptides also inhibit platelet binding of human fibrinogen fragment X and rat fibrinogen, which lack RGDS sequences corresponding to A alpha 572-575. Thus competition between free RGD-containing peptides and internal RGDS sequence at A alpha 572-575 is not the basis for their inhibition of fibrinogen binding to platelets. Addition of a Thr to the carboxy-terminus and an Asn to the amino-terminus of the RGDS sequence, the amino acids corresponding to A alpha 576 and 571 respectively, reduced the inhibitory potency of RGDS-containing peptides by fourfold to tenfold. Arg-Gly-Asp-Phe (RGDF) corresponds to A alpha 95-98, and the RGDF peptide was an effective inhibitor of fibrinogen binding, fourfold to fivefold more potent than RGDS. Thus, local primary structure may play an important role in regulating the capacity of RGD sequences in proteins to interact with specific adhesion receptors.

Adenosine Diphosphate↗
PubMed1988

Restrained refinement of two crystalline forms of yeast aspartic acid and phenylalanine transfer RNA crystals.

Four transfer RNA crystals, the monoclinic and orthorhombic forms of yeast tRNA(Phe) as well as forms A and B of yeast tRNA(Asp), have been submitted to the same restrained least-squares refinement program and refined to an R factor well below 20% for about 4500 reflections between 10 and 3 A. In yeast tRNA(Asp) crystals the molecules exist as dimers with base pairings of the anticodon (AC) triplets and labilization of the tertiary interaction between one invariant guanine of the dihydrouridine (D) loop and the invariant cytosine of the thymine (T) loop (G19-C56). In yeast tRNA(Phe) crystals, the molecules exist as monomers with only weak intermolecular packing contacts between symmetry-related molecules. Despite this, the tertiary folds of the L-shaped tRNA structures are identical when allowance is made for base sequence changes between tRNA(Phe) and tRNA(Asp). However, the relative mobilities of two regions are inverse in the two structures with the AC loop more mobile than the D loop in tRNA(Phe) and the D loop more mobile than the AC loop in tRNA(Asp). In addition, the T loop becomes mobile in tRNA(Asp). The present refinements were performed to exclude packing effects or refinement bias as possible sources of such differential dynamic behavior. It is concluded that the transfer of flexibility from the anticodon to the D- and T-loop region in tRNA(Asp) is not a crystal-line artefact. Further, analysis of the four structures supports a mechanism for the flexibility transfer through base stacking in the AC loop and concomitant variations in twist angles between base pairs of the anticodon helix which propagate up to the D- and T-loop region.

Anticodon↗