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PubMed2003

Inhibition of LPS-responses by synthetic peptides derived from LBP associates with the ability of the peptides to block LBP-LPS interaction.

The ability of LPS-binding protein (LBP) to greatly potentiate cell responses to lipopolysaccharide (LPS) may largely contribute to LPS toxicity in sepsis. The study of agents with the capacity to block the interaction between LBP and LPS might improve the understanding of the role of LBP in Gram-negative infections as well as offering new therapeutic tools for septic disorders. Here we confirm the ability of synthetic peptides comprising the human LBP amino acid region 86-108 to interfere with the LBP-LPS interaction. The analysis of selected alanine mutants of a blocking peptide corresponding to the LBP region 86-99 suggests the importance of peptide amphipathicity for the inhibitory activity. The potency of the native peptide and a selected analogue at inhibiting in vitro and in vivo LPS-induced responses was associated with their relative activity in blocking LBP-LPS interaction. It was remarkable that these peptides were at least 500-fold more active in vivo than in vitro. Also, the inhibitory activity of peptides LBP86-99 and LBPK95A seems to be independent of LBP concentrations, a behavior that may be relevant for the potential use of these peptides in septic disorders where LBP serum concentrations are considerably elevated.

Acute-Phase Proteins↗

PubMed2006

Cytotoxic T cells generated against heteroclitic peptides kill primary tumor cells independent of the binding affinity of the native tumor antigen peptide.

Heteroclitic peptide modifications increase immunogenicity, allowing generation of cytotoxic T lymphocytes (CTLs) against weakly immunogenic tumor-associated antigens (TAAs). A critical issue is whether T cells generated against heteroclitic peptides retain the ability to recognize and kill tumor cells expressing the original weak TAAs, and whether there is a lower threshold of binding affinity of the native peptides, below which such CTLs can still kill primary tumor cells. To examine this we used a model examining the ability of native and heteroclitic immunoglobulin (Ig)-derived peptides to generate CTLs that can kill chronic lymphocytic leukemia (CLL) cells. We demonstrate that CTLs generated against heteroclitic peptides have enhanced killing of CD40-activated B cells pulsed with either heteroclitic (P < .001) or native peptide (P = .04) and primary CLL cells (P = .01). The novel finding reported here is that the rate-limiting factor appears to be the ability to generate CTLs and that once generated, CTL lysis of primary tumor cells is independent of the binding affinity of the native peptide. These findings have implications for vaccination strategies in malignancies and are currently being further examined in vivo in murine models.

Animals↗

PubMed2005

Neutrophil NADPH-oxidase activation by an annexin AI peptide is transduced by the formyl peptide receptor (FPR), whereas an inhibitory signal is generated independently of the FPR family receptors.

Truncation of the N-terminal part of the calcium-regulated and phospholipid-binding protein annexin AI has been shown to change the functional properties of the protein and to generate immunoregulatory peptides. Proinflammatory as well as anti-inflammatory signals are triggered by these peptides, and the two formyl peptide receptor (FPR) family members expressed in neutrophils, FPR and FPR-like 1 (FPRL1), have been suggested to transduce these signals. We now report that an annexin AI peptide (Ac9-25) activates, as well as inhibits, the neutrophil release of superoxide anions. Results obtained from experiments with receptor antagonists/inhibitors, desensitized cells, and transfected cells reveal that the Ac9-25 peptide activates the neutrophil reduced nicotinamide adenine dinucleotide phosphate oxidase through FPR but not through FPRL1. The Ac9-25 peptide also inhibits the oxidase activity in neutrophils triggered, not only by the FPR-specific agonist N-formyl-Met-Leu-Phe but also by several other agonists operating through different G protein-coupled receptors. Our data show that the two signals generated by the Ac9-25 peptide are transmitted through different receptors, the inhibitory signal being transduced by a not-yet identified receptor distinct from FPR and FPRL1.

Annexin A1↗

PubMed1985

Soluble metalloendopeptidase from rat brain: action on enkephalin-containing peptides and other bioactive peptides.

A soluble metalloendopeptidase identified in rat brain, preferentially cleaves bonds in peptides having hydrophobic amino acid residues in the P1, P2, and P3' positions. (The nomenclature of T. Schechter and A. Berger is used to describe the interaction between enzyme and substrate. The amino acid residues in the substrate are designated as P1, P2, P3 etc. in the N-terminal direction and P1', P2', P3' etc. in the C-terminal direction from the bond undergoing cleavage. The corresponding subsites in the enzyme are identified by the letter S.) The degradation of a series of biologically active peptides and their affinity toward the enzyme was studied. Dynorphin-(1-8), alpha-neo-endorphin, and beta-neo-endorphin are rapidly hydrolyzed to form leu-enkephalin, whereas bovine adrenal medulla dodecapeptide is hydrolyzed to form met-enkephalin. The enzyme, however, does not cleave a larger precursor molecule of metenkephalin, such as bovine adrenal medulla docosapeptide. Several other bioactive peptides are also cleaved at sites consistent with our previously reported specificity studies. Met- and leu-enkephalin are resistant to hydrolysis. The binding affinity [as expressed by inhibitory constant (Ki) or Michaelis-Menten constant (Km) values] of several bioactive peptides such as dynorphin-(1-8), beta-neo-endorphin, neurotensin, angiotensin I, and bradykinin was found to be in the micromolar range. These peptides were also rapidly hydrolyzed by the enzyme, showing, as a result, high specificity constants (kcat/Km values). The highest enzyme activity was found in brain, testis, and in the anterior and posterior lobes of the pituitary, while the activity in such tissues as spleen, liver, kidney, lung, adrenals, and thyroid amounted to only 10-20% of that found in brain. This distribution of enzyme activity, together with its preference for oligopeptides as substrates, its ability to generate leu- and met-enkephalin from several larger peptide precursors, and its affinity toward several other bioactive peptides, suggests that the enzyme functions in the metabolism of neuropeptides.

Animals↗

PubMed1996

Peptide T in the treatment of painful distal neuropathy associated with AIDS: results of a placebo-controlled trial. The Peptide T Neuropathy Study Group.

OBJECTIVE: To assess the safety and efficacy of Peptide T in the treatment of painful distal symmetrical polyneuropathy (DSP) associated with human immunodeficiency virus (HIV) infection. BACKGROUND: Painful DSP is a frequent complication of HIV infection, although its etiology and optimal treatment are unknown. Peptide T (D-(alpha 1)-Peptide T-amide) has been found in phase I trials and anecdotal reports to relieve neuropathic pain in AIDS patients. DESIGN/METHODS: In this multicentered, double-blind, randomized study, subjects received intranasal Peptide T 6 mg/day or placebo for 12 weeks. The primary outcome measure was change in the modified Gracely pain score. Secondary efficacy variables were results of neurologic examination, neuropsychological and electrophysiologic studies, global evaluation, and CD4 lymphocyte counts. RESULTS: Of 81 evaluable subjects, 40 received Peptide T and 41 received placebo. The change in pain scores was not significantly different (p = 0.32) in the Peptide T group (-0.24) as compared to placebo (-0.39). Group comparisons were not significantly different for change in any clinical examination or neuropsychologic measure, sural nerve amplitude or conduction velocity, or CD4 lymphocyte count. No significant drug-related adverse effects occurred in either group. CONCLUSION: Intranasal Peptide T is safe but ineffective in the treatment of painful DSP associated with AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Amino acids and peptides. XXVII. Synthesis of phytochelatin-related peptides and examination of their heavy metal-binding properties.

Phytochelatin (PC)-related peptides were prepared by a conventional solution method and their heavy metal-binding properties were examined. Different from the Cu2+ and Cu+ -binding properties of metallothionein (MT)-related peptides, the Cu2+ and Cu+ -binding properties of PC-related peptides were fairly dependent on structure. It is of interest that gamma-Glu-Cys-Gly (glutathione) exhibited quite different Cu2+ and Cu+ -binding properties from those of other PC-related peptides and its binding abilities were comparable to those of MT-related peptides. The Cd2+ -binding properties of glutathione were similar to those of Cys, and the Cd2+ -binding abilities of PC-related peptides increased in proportion to the increase of gamma-Glu-Cys peptide unit.

Amino Acid Sequence↗

PubMed1999

Amino acids and peptides. LV. Application of 2-adamantyl derivatives as protecting groups to the synthesis of peptide fragments related to Sulfolobus solifataricus ribonuclease. II.

Segment condensations were performed to construct peptide fragments related to Sulfolobus solifataricus Ribonuclease. At each condensation step, the new protecting groups were stable. The protected peptide fragments were treated with a low-high HF procedure to give the desired peptide fragments. These peptide fragments were also prepared by the solid-phase method, and the obtained peptides were compared with those obtained by the solution method. The peptide fragments obtained by the solution method were identical with those obtained by the solid-phase method on analytical HPLC, indicating that the new protecting groups could be easily removed by HF, and no racemization occurred during the synthesis of the protected peptides.

Adamantane↗

PubMed2002

Dynamic characteristics of a peptide-binding groove of human HLA-A2 class I MHC molecules: normal mode analysis of the antigen peptide-class I MHC complex.

Class I major histocompatibility complex (MHC) binds antigen peptides with various sequences. We performed a normal mode analysis of HLA-A2 MHC that binds three peptides with different affinity. HLA-A2 MHC has a peptide-binding groove composed of two alpha-helices (residue 49-84, residue 140-179). Some residues in the center of the groove showed an increase in fluctuations and some residue pairs between two helix groups showed a negative change in correlations by removing the antigen peptide. The extent of the fluctuation and correlation changes correlated well with the experimental ranking of the three peptides in binding affinity. Some definite anti-correlative motions were found between two helix groups in low frequency modes (<50 cm(-1)) by removing the antigen peptide. We propose that the above anti-correlative motions play an important role to bind the antigen peptide, especially in obtaining a "dynamic fit."

Crystallography, X-Ray↗

PubMed1993

[Pharmacological studies on small peptide fraction derived from soybean. The effects of small peptide fraction derived from soybean on fatigue, obesity and glycemia in mice].

The present research was an attempt to determine the pharmacological actions as for anti-fatigue, anti-obesity and hypoglycemia of small peptide isolated from soybean in mice. Small peptide administration prevented the decrease in sporting movement induced by concussion stress for 3 h in mice. In addition, it should be noted that the recovery rate of fatigue in 60 min after small peptide administration was over one hundred percentage in comparison with that after pretreatment, while the equivalent dose administration of amino acid mixture with the same small peptide amino acid composition did not prevent the decrease in sporting movement. In gold-thioglucose (500 mg/kg (i.p.))-induced obese mouse body weight gain, liver weight and body lipid level around uterine were significantly reduced by the chronic oral administration of small peptide (200, 1000 mg/kg). Administration in 1000 mg per kg of small peptide significantly lowered hyperglycemia in 30 and 120 min after glucose (3 g/kg (p.o.)) administration, whereas the equivalent amino acid mixture showed no effect. In conclusion, it suggested that small peptide isolated from soybean might have some pharmacological effects of anti-fatigue, anti-obesity, and hypoglycemia.

Animals↗

PubMed1998

Peptide models of immunological recognition: paratope dissection by multiple peptide synthesis.

New approaches to obtain information about the residues of the antibody paratope involved in the interaction with antigen would be very useful to help perform rational mutagenesis of antibodies for improving sensitivity or selectivity in immunoassays. We have evaluated the possibility of dissecting the antibody paratope into large sets of short (12 residues) overlapping peptides to determine the contribution of each peptide to antigen binding. Our results show that the systematic analysis of the antigen-binding properties of heavy chain variable segment and light chain variable segment derived peptides of HyHEL-5, a model anti-lysozyme antibody, can be an experimental approach to the selection of paratope-derived peptides with antigen-binding activity. Detailed analysis of the contribution of each residue from each binding peptide permitted the identification of residues contributing to antigen binding. Of the 38 residues we identified, 22 corresponded to residues that had been shown by X-ray crystallography to be at the interface between HyHEL-5 and lysozyme. The peptide analysis we have developed is thus a way to map the subset of residues from the antibody paratope involved in antigen recognition. The same peptide approach was used to map the idiotope that an anti-idiotypic antibody recognized in the paratope of its cognate antibody.

Antibodies, Anti-Idiotypic↗

PubMed2002

Antibiotic activity of reversed peptides of alpha-helical antimicrobial peptide, P18.

P18 (KWKLFKKIPKFLHLAKKF-NH(2)), an a-helical antimicrobial peptide designed from cecropin Amagainin 2 hybrid, was known to have potent antimicrobial activity against bacteria as well as fungi without hemolytic activity. To find the peptides comparable or superior to the antimicrobial activity of P18, the two reversed peptides (Rev-1 and Rev-2) of P18 were designed and synthesized. These peptides were found to have similar antimicrobial activity against bacterial and fungal cells without hemolytic activity as compared with P18. Furthermore, a reversed peptide, Rev-2 was shown to have a two-fold higher activity in killing some bacterial cells than P18. Therefore, these results suggested that Rev-2 peptide seems to be an excellent candidate for developing novel peptide antibiotics.

Amino Acid Sequence↗

PubMed2002

The central role played by peptides in the immune response and the design of peptide-based vaccines against infectious diseases and cancer.

Vaccines are one of the most cost effective methods of improving public health thereby increasing the quality of life. Prophylactic and therapeutic treatment by vaccines can prevent infectious diseases and some cancers and could also be used in the treatment of autoimmune disorders. An appreciation of this potential has resulted in a burgeoning literature which not only describes the scientific efforts being made into designing new and improved vaccines but also drives the efforts being made by public health organizations world-wide in delivering vaccines to the community. At the forefront of technologies being applied to the design of vaccines is the use of synthetic peptides; the chemical technologies used to assemble peptides have made great strides over the last decade and assembly of hi-fidelity peptides which can be of high molecular weight, multimeric or even branched is now almost routine. Together with the advances in peptide technology our understanding of the molecular events that are necessary to induce immune responses has also made great strides. The central role that peptides play in immune recognition is now recognised and rules are emerging that are being applied to the construction of peptide-based vaccines that, in the right context, can induce humoral (antibody) and cellular (cytotoxic and helper T cell) immune responses. Synthetic peptides are exquisitely placed to answer questions about immune recognition and along the way to provide us with new and improved vaccines.

Animals↗

PubMed1988

Day-long integrated serum insulin and C-peptide profiles in patients with NIDDM. Correlation with urinary C-peptide excretion.

To determine whether non-insulin-dependent diabetes mellitus (NIDDM) is characterized by day-long hypoinsulinemia, we measured 24-h serum profiles for glucose, insulin, and C-peptide by use of a constant-rate blood-withdrawal technique in diabetic and control subjects fed isocaloric meals. When only lean subjects were considered, diabetic subjects (relative body weight 0.99 +/- 0.3) and control subjects (relative body weight 0.95 +/- 0.03) had similar 24-h integrated serum insulin concentrations (13.4 +/- 2.5 vs. 16.1 +/- 2.0 microU/ml, P NS) due to the offsetting effects of increased basal levels and decreased postprandial responses in NIDDM. In contrast, both basal and meal-stimulated insulin levels were decreased in obese NIDDM subjects (relative body weight 1.39 +/- 0.07) compared with obese control subjects (relative body weight 1.60 +/- 0.08), resulting in a 61% reduction in the 24-h integrated insulin value (18.7 +/- 1.5 vs. 48.4 +/- 13.7 microU/ml). Thus, the capacity to increase 24-h integrated serum insulin as a function of relative body weight was impaired in NIDDM subjects (r = 0.27, P NS) compared with control subjects (r = .70, P less than .01). In contrast, 24-h integrated C-peptide was decreased (P less than .01) in both lean (0.92 +/- 0.13 pM/ml) and obese (1.52 +/- 0.19 pM/ml) NIDDM patients compared with the respective control groups (1.50 +/- 0.13 and 3.03 +/- 0.44 pM/ml). The molar ratio of 24-h integrated C-peptide to insulin was diminished in lean but not obese NIDDM compared with control subjects. A 3-wk period of intensive insulin therapy led to normalization of the mean 24-h integrated insulin (but not integrated serum C-peptide) value in NIDDM compared with a control group that had an identical mean relative body weight. The 24-h urinary C-peptide measured on the same day as the serum profile was correlated (P less than .01) with both the 24-h integrated serum insulin (r = .69) and C-peptide (r = .67) concentrations in control subjects but not in NIDDM subjects (r = .20 and .04, respectively, P NS). Additionally, the urinary clearance of C-peptide was increased in NIDDM (38.1 +/- 7.8 vs. 20.4 +/- 1.7 ml/min in control subjects, P less than .05) and varied with treatment status (26.0 +/- 4.6 ml/min after insulin therapy).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1991

Antisense peptides: tools for receptor isolation? Lack of antisense MSH and ACTH to interact with their sense peptides and to induce receptor-specific antibodies.

The use of antisense peptides for receptor isolation as proposed by Blalock and his colleagues (e.g. TIBTECH 8, 140-144, 1990) was tested for human ACTH as well as alpha- and beta-MSH. We synthesized the corresponding antisense peptides HTCAh, HSM-alpha and HSM-beta and analyzed them for specific interaction with the sense peptides using several types of binding assay and bioassay. Similarly HTCAh antibodies were tested for binding to ACTH receptors and ACTH antibodies. All these experiments were negative, i.e. there was no specific interaction between sense and antisense peptides nor between the corresponding antibodies. Receptor binding of the sense peptides was not affected by the antisense peptides or HTCAh antibodies. Unexpectedly, HTCAh but not HSM-alpha or HSM-beta was a weak MSH agonist acting through a site independent of the MSH receptor. A detailed analysis of the concept of antisense peptides revealed that the theoretical background of the hypothesis of the 'molecular recognition theory' is rather weak, explaining the failure of various attempts to obtain specific receptor antibodies.

Adrenocorticotropic Hormone↗

PubMed2001

Naturally processed HLA class II peptides reveal highly conserved immunogenic flanking region sequence preferences that reflect antigen processing rather than peptide-MHC interactions.

MHC class II heterodimers bind peptides 12-20 aa in length. The peptide flanking residues (PFRs) of these ligands extend from a central binding core consisting of nine amino acids. Increasing evidence suggests that the PFRs can alter the immunogenicity of T cell epitopes. We have previously noted that eluted peptide pool sequence data derived from an MHC class II Ag reflect patterns of enrichment not only in the core binding region but also in the PFRS: We sought to distinguish whether these enrichments reflect cellular processes or direct MHC-peptide interactions. Using the multiple sclerosis-associated allele HLA-DR2, pool sequence data from naturally processed ligands were compared with the patterns of enrichment obtained by binding semicombinatorial peptide libraries to empty HLA-DR2 molecules. Naturally processed ligands revealed patterns of enrichment reflecting both the binding motif of HLA-DR2 (position (P)1, aliphatic; P4, bulky hydrophobic; and P6, polar) as well as the nonbound flanking regions, including acidic residues at the N terminus and basic residues at the C terminus. These PFR enrichments were independent of MHC-peptide interactions. Further studies revealed similar patterns in nine other HLA alleles, with the C-terminal basic residues being as highly conserved as the previously described N-terminal prolines of MHC class II ligands. There is evidence that addition of C-terminal basic PFRs to known peptide epitopes is able to enhance both processing as well as T cell activation. Recognition of these allele-transcending patterns in the PFRs may prove useful in epitope identification and vaccine design.

Amino Acid Motifs↗

PubMed2001

Anti-peptide antibody blocks peptide binding to MHC class I molecules in the endoplasmic reticulum.

The finding that MHC class I molecules are physically associated with the TAP transporter has suggested that peptides may be directly transported into the binding groove of the class I molecules rather than into the lumen of the endoplasmic reticulum (ER) where they subsequently would encounter class I molecules by diffusion. Such a mechanism would protect peptides from peptidases in the ER and/or escaping back into the cytoplasm. However, we find that an anti-peptide Ab that is cotranslationally transported into the ER prevents TAP-transported peptides from being presented on class I molecules. The Ab only blocks the binding of its cognate peptide (SIINFEKL) but not other peptides (KVVRFKDL, ASNENMETM, and FAPGNYPAL). Therefore, most TAP-transported peptides must diffuse through the lumen of the ER before binding stably to MHC class I molecules.

ATP-Binding Cassette Transporters↗

PubMed1999

Stable peptide binding to MHC class II molecule is rapid and is determined by a receptive conformation shaped by prior association with low affinity peptides.

Formation of stable class II MHC/peptide complex involves conformational changes and proceeds via an intermediate. Although this intermediate complex forms and dissociates in minutes, its conversion to a stable complex is a very slow process, taking up to a few days to reach completion. Here, we investigate the different steps of this binding and demonstrate that the conformational changes necessary to generate a receptive molecule is the rate-determining slow step in the process, while formation of the stable MHC/peptide complex is very rapid. With HLA-DR1 as our model class II molecule, we first used low affinity variants of hemagglutinin peptide (HA306-318), which lack the principal anchor, to shape the conformation of the MHC and then studied the kinetics of stable binding of HA306-318 to such an induced conformation. We found that the apparent association rate of HA306-318 is equivalent to the dissociation rate of the low affinity peptide. A 4- to 18-fold enhancement in the binding rates of HA306-318 was observed depending on the dissociation rates of the low affinity peptides. These results establish that 1) formation of stable MHC/peptide complexes is very rapid and 2) prior binding of low affinity peptide induces a receptive conformation in MHC for efficient stable peptide binding. Furthermore, in the absence of any free peptide, this receptive molecule rapidly reverts to slow binding behavior toward the subsequently offered peptide. These results have important implications for the roles of low affinity MHC/peptide complexes in Ag presentation.

Antigens, Viral↗

PubMed2000

High-affinity binding of peptide agonists to the human B1 bradykinin receptor depends on interaction between the peptide N-terminal L-lysine and the fourth extracellular domain of the receptor.

The aim of this study was to identify the location of the N terminus of peptide agonist ligands when bound to the human B1 bradykinin (BK) receptor. To reach this aim, we exploited the fact that high-affinity binding of kinin peptides to the human B1 receptor subtype requires a peptide N-terminal L-Lys, whereas high-affinity binding to the B2 receptor subtype does not require this residue. This was done by comparing the affinities of BK, a B2 receptor-selective peptide, and kallidin or Lys-BK, a less receptor-selective peptide, for chimeric proteins in which each B1 receptor domain had been substituted in the human B2 receptor and expressed in HEK293 cells. Individual substitution of transmembrane domains 1-7 (TM-I-VII) and extracellular domains 1-4 (EC-I-IV) of the B1 receptor in the B2 receptor influenced the affinities of BK and Lys-BK approximately equally. In contrast, substitution of B1 EC-IV dramatically reduced the affinity and potency of BK, whereas these parameters for Lys-BK were essentially unaltered. Substitution of either the N- or C-terminal half of B1 EC-IV in the B2 receptor only had a limited effect on the peptide binding constants, indicating the involvement of multiple residues throughout this domain. Complementary mutations of the N-terminal residue in Lys-BK revealed that both the positive charge and the proper spatial orientation of this residue were required for interaction with B1 EC-IV. Thus, the N-terminal residue of peptide agonists when bound to the human B1 receptor is positioned extracellularly and interacts with EC-IV.

Amino Acid Sequence↗