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PubMed1998

Design and synthesis of small semi-mimetic peptides with immunomodulatory activity based on myelin basic protein (MBP).

Experimental allergic encephalomyelitis (EAE) is induced in susceptible animals by immunodominant determinants of myelin basic protein (MBP). Analogs of these disease-associated peptides have been identified with disease progression upon coimmunization. Usage of peptides, with disease-specific immunomodulatory capacity in vivo is limited, however, due to their sensitivity to proteolytic enzymes. Alternative approaches include the development of mimetic molecules which maintain the biological function of an original peptide, yet are stable and able to elicit their response in pharmacological quantities. A novel technique was employed to design a series of semi-mimetic peptides, based on the guinea pig MBP72-85 peptide used to induce EAE in Lewis rats. We used isonipecotic (iNip) and aminocaproic (Acp) acids as templates. Acp-MBP72-85 peptide derived analogues were effective in inducing EAE compared to iNip-peptide analogues which were ineffective at 350 micrograms. These findings suggest that the design and synthesis of semi-mimetic peptide molecules with immunomodulatory potential is possible and that eventually these molecules may form the basis for the development of novel and more effective disease-specific therapeutic agents.

Amino Acid Sequence↗
PubMed1999

Surface interactions of a homologous series of alpha,omega-amino acids on colloidal silver and gold.

Surface enhanced Raman spectroscopy (SERS) was used to characterize a homologous series of alpha,omega-amino acids on colloidal gold and silver. Raman and SER spectra of the alpha,omega-amino acids, NH2(CH2)nCOOH (n = 3-7), are presented and analyzed, revealing the probable conformations of the molecules on the metal surfaces. The alpha,omega-amino acids interact with silver and gold through both the amine and carboxylate end groups, and modify the conformation of the molecular backbone in order to maximize these interactions. An odd-even effect is observed for backbone conformations of molecules adsorbed to the silver substrate. The anomolous SER spectrum of 5-aminopentanoic acid on gold suggests the possibility of condensation polymerization at the gold surface.

Alkanes↗
PubMed1996

Crystal structures of apolipoprotein(a) kringle IV37 free and complexed with 6-aminohexanoic acid and with p-aminomethylbenzoic acid: existence of novel and expected binding modes.

Kringles are protein modules found within a wide variety of fibrinolytic and coagulation-related proteins that show binding affinity for lysine, lysine analogs and for fibrin. We report here the crystal structures of apolipoprotein(a) kringle IV37 (apo(a) K4(37)) in its free state and in separate complexes with two omega-amino acids, 6-aminohexanoic acid (6AHA) and p-aminomethylbenzoic acid (PAMBA). The structures of the unliganded form and of both complexes have been determined and refined by restrained least-squares methods to about 2.0 angstrom. The overall kringle architecture is essentially identical with that determined in other kringles but it shows some small significant structural changes in the lysine binding site. Ther is virtually no difference in conformation between the unliganded and complexed forms, suggesting that apo(a) K4(37) does not undergo any conformational rearrangement upon binding. The 6AHA molecule binds to apo(a) K4(37) in a completely different way from that observed with the kringle 4 of plasminogen (PGK4). Its amino group makes an ion pair interaction with the two aspartate residues (Asp55/Asp57) of the anionic center and its carboxylate group faces out into the solvent making water-mediated contacts with the protein. The mode of binding of PAMBA resembles more that decribed for 6AHA when bound to PGK4. The PAMBA molecule is bound by ion pair interactions with the two aspartate residues (Asp55/Asp57) and with Arg71 from the cationic center and by van der Waals contacts. The relative importance of the cationic center from kringles for binding zwitterionic ligands is discussed.

4-Aminobenzoic Acid↗
PubMed1994

Differential effects of vigabatrin, gamma-acetylenic GABA, aminooxyacetic acid, and valproate on levels of various amino acids in rat brain regions and plasma.

Drugs which elevate brain levels of the inhibitory amino acid neurotransmitter GABA by inhibiting the GABA catabolizing enzyme GABA transaminase (GABA-T) have been developed for treatment of brain disease, such as epilepsy. Among all GABA-T inhibitors available, vigabatrin is thought to be the most selective compound, and this drug is the only GABA-T inhibitor in clinical use. However, some previous studies have indicated that vigabatrin might affect the metabolism of several amino acids not directly linked to the GABA shunt. In the present study, various amino acids, involving inhibitory and excitatory neurotransmitters, were determined in 12 brain regions and plasma of rats after treatment with anticonvulsant doses of vigabatrin and the less selective GABA-T inhibitors aminooxyacetic acid (AOAA) and gamma-acetylenic GABA (GAG). Furthermore, the antiepileptic drug valproate, which is also thought to act via the GABA system, was included for comparison. The GABA-T inhibitors markedly enhanced GABA levels in all brain regions examined, while valproate induced only moderate increases in some regions. All drugs, including valproate, significantly decreased aspartate in the brain to a similar extent, and the GABA-T inhibitors but not valproate decreased levels of glutamate. The decreases in aspartate and glutamate levels were not correlated with the different magnitudes of GABA increase produced by GABA-T inhibitors, suggesting that these effects were not simply due to the altered GABA degradation. In addition to glutamate and aspartate, alanine levels were decreased by GABA-T inhibitors but not valproate in several regions. Brain levels of glutamine were decreased by GAG and vigabatrin but increased by valproate and partly also by AOAA.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkynes↗
PubMed1984

Synergistic anticonvulsant effects of GABA-T inhibitors and glycine.

The anticonvulsant effect of inhibitors of GABA-T (R/S-gamma-vinyl-GABA, ethanolamine-O-sulfate, gabaculine, aminooxyacetic acid) was enhanced by 10 mmol/kg glycine in animal seizure models which are based on a functional GABA deficit. Similar to glycine in their action, although less effective, were its close structural analogues (sarcosine, N,N-dimethylglycine) and homologous omega-aminoacids (beta-alanine, taurine, gamma-aminobutyric acid, delta-aminovaleric acid). It is assumed that glycine and its structural analogues act on supraspinal glycine receptors as glycine agonists. Our observation is the first example of the synergistic interaction of two inhibitory neuronal systems resulting in the amplification of the anticonvulsant effect. Combined treatment with GABA-T inhibitors and glycine may turn out to be of practical importance in the therapy of seizure disorders and other diseases, for which treatment with GABA-T inhibitors is considered a potentially useful therapeutic approach.

3-Mercaptopropionic Acid↗
PubMed1992

Direct identification of lysine-33 as the principal cationic center of the omega-amino acid binding site of the recombinant kringle 2 domain of tissue-type plasminogen activator.

We have generated site-specific mutants of the kringle 2 domain of tissue-type plasminogen activator [( K2tPA]) in order to identify directly the cationic center of the protein that is responsible for its interaction with the carboxyl group of important omega-amino acid effector molecules, such as epsilon-amino caproic acid (EACA). Molecular modeling of [K2tPA], docked with EACA, based on crystal structures of the kringle 2 region of prothrombin and the kringle 4 domain of human plasminogen, clearly shows that Lys33 is the only positively charged amino acid in [K2tPA] that is sufficiently proximal to the carboxyl group of the ligand to stabilize this interaction. In order to examine directly the importance of this particular amino acid residue in this interaction, we have constructed, expressed, and purified three recombinant (r) mutants of [K2tPA], viz., Lys33Thr, Lys33Leu, and Lys33Arg, and found that only the last variant retained significant ability to interact with EACA and several of its structural analogues at neutral pH. In addition, another mutated r-[K2tPA], i.e., Lys33His, interacts very weakly with omega-amino acids at neutral pH and much more strongly at lower pH values where His33 would be expected to undergo protonation. This demonstrates that any positively charged amino acid at position 33 satisfies the requirement for mediation of significant bindings to this class of molecules. Since, in other kringles, positively charged residues at amino acid sequence positions homologous to Lys68, Arg70, and Arg71 of [K2tPA] have been found to participate in kringle interactions with EACA-like compounds, we have also examined the binding of EACA, and some of its analogues, to three additional r-[K2tPA] variants, i.e., Lys68Ala, Arg70Ala, and Arg71Ala. In each case, binding of these omega-amino acids to the variant kringles was observed, with only the Lys68Ala variant showing a slightly diminished capacity for this interaction. These investigations provide clear and direct evidence that Lys33 is the principal cationic site in wild-type r-[K2tPA] that directly interacts with the carboxyl group of omega-amino acid effector molecules.

Amino Acid Sequence↗
PubMed1991

Solution structure of the tissue-type plasminogen activator kringle 2 domain complexed to 6-aminohexanoic acid an antifibrinolytic drug.

The solution structure of a recombinant tissue-type plasminogen activator kringle 2 domain, complexed with the antifibrinolytic drug 6-aminohexanoic acid (6-AHA) was determined via 1H nuclear magnetic resonance spectroscopy and dynamical simulated annealing calculations. The structure determination is based on 610 intramolecular kringle 2 and 14 intermolecular kringle 2-6-AHA interproton distance restraints, as well as on 82 torsion angle restraints. Three sets of simulated annealing structures were computed from three different classes of starting structures: (1) random conformations devoid of disulfide bridges; (2) random conformations that contain correct disulfide bonds; and (3) a folded conformation modeled after the homologous prothrombin kringle 1 X-ray crystallographic structure. All three sets of structures are well defined, with averaged atomic root-mean-square deviations between individual structures and mean set structures of 0.77, 0.99 and 0.70 A for backbone atoms, and 1.36, 1.55 and 1.41 A for all atoms, respectively. Kringle 2 is an oblate ellipsoid with overall dimensions of approximately 34 A x 30 A x 17 A. It exhibits a compact globular conformation characterized by a number of turns and loop elements as well as by one right-handed alpha-helix and five (1 extended and 4 rudimentary) antiparallel beta-sheets. The extended beta-sheet exhibits a right-handed twist. Close van der Waals' contacts between the Cys22-Cys63 and Cys51-Cys75 disulfide bridges and the central hydrophobic core composed of the Trp25, Leu46, His48a and Trp62 side-chains are among the distinguishing features of the kringle 2 fold. The binding site for 6-AHA appears as a rather exposed cleft with a negatively charged locus defined by the Asp55 and Asp57 side-chains, and with an aromatic pocket structured by the Tyr36, Trp62, His64 and Trp72 side-chains. The Trp62 and His64 rings line the back surface of the pocket, while the Tyr36 and Trp72 rings confine it from two sides. The Trp62 and Trp72 indole rings conform a V-shaped groove. The methyl groups of Val35 also contribute lipophilic character to the ligand-interacting surface. It is suggested that the positively charged side-chains of Lys34 and, potentially, Arg69 may favor interactions with the carboxylate group of the ligand. The Trp25 and Tyr74 aromatic rings, although conserved elements of the binding site structure, seem not to undergo direct contacts with the ligand.

Amino Acid Sequence↗
PubMed1994

Effects of alpha 2-plasmin inhibitor on plasminogen activation by staphylokinase/plasminogen complex.

Using a stable cross-linked SAK/plg complex, the effects of alpha 2-plasmin inhibitor on plasminogen activation by SAK were investigated. alpha 2-Plasmin inhibitor inhibited dose-dependently plasminogen activation by the SAK/plg complex. When FCB-2 or EACA was added to the reaction mixture of SAK/plg complex and alpha 2-plasmin inhibitor, the inhibitory activity of alpha 2-plasmin inhibitor was abolished and the enzymatic activity of the complexes was restored. alpha 2-Plasmin inhibitor inhibited the activity of the SK/plg complex, but neither FCB-2 nor EACA restored the plasminogen activator activity in the mixture of SK/plg complex and alpha 2-plasmin inhibitor. Using 125I-labeled SAK/plg complex or SK/plg complex, the reaction of the complex with alpha 2-plasmin inhibitor was analyzed. The SAK/plg complex produced a new complex with alpha 2-plasmin inhibitor. The formation of a new high molecular weight complex with alpha 2-plasmin inhibitor was abolished by both EACA or FCB-2. With regard to the SK/plg complex, neither EACA nor FCB-2 suppressed the complex formation with alpha 2-plasmin inhibitor. These findings indicate that the SAK/plg complex binds to fibrin, and that this complex expresses plasminogen activator activity without being affected by alpha 2-plasmin inhibitor.

Amino Acid Sequence↗
PubMed1995

Effect of fucoidan during activation of human plasminogen.

Fucoidan [sulfated poly (L-fucopyranose)] was compared with 6-aminohexanoic acid (6-AH) or CNBr-cleaved fibrinogen (CNBr-Fbg) alone or in combination in enhancing the activation of glutamic plasminogen (Glu-Plg) or lysine plasminogen (Lys-Plg) by two-chain tissue plasminogen activator (t-PA) or LMwt-urokinase or by streptokinase. Fucoidan enhanced the t-PA activation of Glu-Plg or Lys-Plg at Plg concentrations greater than 75nM, while stimulation by CNBr-Fbg of t-PA activation followed saturation kinetics of Michaelis-Menton. During t-PA activation of Glu-Plg, a high degree of synergism was observed between 6-AH and fucoidan while the enhancement by CNBr-Fbg was not influenced by fucoidan and was reversed by 6-AH. Fucoidan alone at higher concentrations was effective in enhancing the activation of Glu-Plg by urokinase while the combination of fucoidan and 6-AH showed additive effect in enhancing the activation of Lys-Plg. The activation of Glu-Plg by streptokinase was reversed by fucoidan in a manner similar to that reported for 6-AH. The results are interpreted to suggest that CNBr-Fbg and 6-AH compete with each other for the same lysine binding sites (LBS) on the Plg molecule while fucoidan acted synergistically with 6-AH in enhancing the t-PA activation of Glu-Plg by a different mechanism. The double reciprocal plot for the interaction of Glu-Plg and urokinase also showed a significantly higher affinity between the two in presence of fucoidan.

Amino Acid Sequence↗
PubMed2006

Strategy for affinity maturation of an antibody with high evolvability to (4-hydroxy-3-nitrophenyl) acetyl hapten.

In order to quantitate the contribution of amino acid replacements to an increase in affinity during affinity maturation, we measured thermodynamic parameters of the antigen-antibody interaction for a group of anti-(4-hydroxy-3-nitrophenyl) acetyl monoclonal antibodies whose differences in amino acid sequences had arisen only from somatic hypermutation. We prepared a common ancestor and hypothetical intermediate clones that might occur on the affinity maturation pathway, by employing site-directed mutagenesis. Isothermal calorimetric titration of the antigen-antibody reaction revealed that antibody evolution proceeds in two steps. The first step is driven by a decrease in enthalpy, in which two amino acid replacements in the VL region play an essential role. Further accumulation of amino acid replacements in VH and VL regions during the second step induce a progressive increase in affinity, which is driven by an increase in entropy, which has a cooperative mutational effect.

Amino Acid Sequence↗
PubMed1995

Activation and characterization of procarboxypeptidase B from human plasma.

Recently we reported the isolation and cloning of a novel plasma procarboxypeptidase B that binds plasminogen [Eaton, D. L., Malloy, B. E., Tsai, S. P., Henzel, W., & Drayna, D. (1991) J. Biol. Chem. 266, 21833-21838]. This plasma procarboxypeptidase is structurally similar to tissue procarboxypeptidases, and initial substrate studies showed that this plasma protein behaves like a basic carboxypeptidase and is now known as human plasma procarboxypeptidase B (pro-pCPB). However, unlike the tissue procarboxypeptidases, pro-pCPB is extremely unstable to trypsin activation. Trypsin cleaves pro-pCPB at two sites: Arg-92 and Arg-330. Cleavage at Arg-92 releases the activation peptide and generates an active enzyme. However, cleavage at Arg-330 inactivates pCPB. This renders the characterization of pCPB difficult. We have found that 6-amino-n-hexanoic acid (epsilon ACA), a compeptitive inhibitor of basic carboxypeptidases, selectively limits trypsin cleavage of pro-pCPB. In the presence of epsilon ACA, trypsin cleavage at Arg-330 is significantly limited while the cleavage at Arg-92 is unaffected. Using this approach, active pCPB can now be obtained. Kinetic characterization shows that pCPB behaves like other known basic carboxypeptidases. pCPB is more specific for substrates with C-terminal arginine than those with C-terminal lysine for all the natural and synthetic peptides tested. It also hydrolyzes the synthetic ester substrate more efficiently than the synthetic peptide substrate, especially at high pH. The active site Zn2+ can be replaced with other metals with change in substrate specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗