Conformational and biological analysis of α-MSH fragment analogues with sterically constrained amino acid residues

1988 ◽  
Vol 53 (11) ◽  
pp. 2549-2573 ◽  
Author(s):  
Victor J. Hruby ◽  
Wayne L. Cody ◽  
Ana Maria de Lauro Castrucci ◽  
Mac E. Hadley
Keyword(s):  
Amino Acid ◽  
Carboxylic Acid ◽  
Aromatic Ring ◽  
Biological Activities ◽  
Three Dimensional ◽  
Amino Acid Side Chain ◽  
Nmr Studies ◽  
Peptide Backbone ◽  
Biological Analysis ◽  
Conformational Properties

Conformational and biological analysis of the linear 4-11 fragment analogues, Ac-[Nle4]-α-MSH4-11-NH2 (II) and Ac-[Nle4, D-Phe7]-α-MSH4-11-NH2 (III) and related analogues have been undertaken. In solution, the peptide backbone is flexible, but in the case of D-Phe7 analogues an interaction of the His6, D-Phe7 and Arg8 amino acid side chain groups may be present based on the shielding patterns observed in the proton NMR and on comparison of NT1 values. The importance of the position 7 to the biological and conformational properties was further examined by substitution of either L- or D-phenylglycine (Pgl) or L- and D-1,2,3,4-tetrahydroisoquinoline carboxylic acid (Tic) for phenylalanine-7. Ac-[Nle4, Pgl7]-α-MSH4-11-NH2 (IV), Ac-[Nle4, D-Pgl7]-α-MSH4-11-NH2 (V), Ac-[Nle4, Tic7]-α-MSH4-11-NH2 (VI), and Ac-[Nle4, D-Tic7]-α-MSH4-11-NH2 (VII) were prepared. These substituted analogues were examined for their biological activities and conformational properties with emphasis on the three-dimensional orientation of the aromatic ring in the position 7, and the effects of the aromatic ring on adjacent amino acids, and on biological activities. The relative potencies of the analogues in the frog skin assay system were: II (1·00); III (118); IV (82·4); V (0·18); VI (0·18); and VII (0·14); and in the lizard skin bioassay they were: II (1·00); III (10·0); IV (0·14); V (0·005); VI (0·00025); and VII (0·01). On the basis of the NMR studies the L-phenylglycine substitution results in an enhanced ring stacking interaction between the phenyl ring of Pgl7 and the indole ring of Trp9. The 1,2,3,4-tetrahydroisoquinoline carboxylic acid (Tic) substitution leads to significant backbone restriction and an interaction of the alpha proton of His6 with the carbonyl of Glu5. The possible relationships of these effects to biological activity are discussed.

Synthesis of a bis-cationic α,α-disubstituted amino acid (9-amino-bispidine-9-carboxylic acid) and its effects on the conformational properties of peptides

Tetrahedron ◽  
2015 ◽  
Vol 71 (15) ◽  
pp. 2241-2245 ◽  
Author(s):  
Hiroko Yamashita ◽  
Yosuke Demizu ◽  
Takashi Misawa ◽  
Takuji Shoda ◽  
Masaaki Kurihara
Keyword(s):  
Amino Acid ◽  
Carboxylic Acid ◽  
Conformational Properties ◽  
Disubstituted Amino Acid

Synthesis and biological properties of vasopressin analogues containing 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

1990 ◽  
Vol 55 (4) ◽  
pp. 1099-1105 ◽  
Author(s):  
Zdenko Procházka ◽  
Juris E. Ancans ◽  
Jiřina Slaninová ◽  
Alena Machová ◽  
Tomislav Barth ◽  
...  
Keyword(s):  
Amino Acid ◽  
Carboxylic Acid ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
Biological Activities ◽  
Biological Properties ◽  
Phase Synthesis ◽  
Aromatic Residues ◽  
Synthesis Methodology ◽  
Vasopressin Analogues

Solid phase synthesis methodology on a benzhydrylamine resin was used for the synthesis of three analogues of vasopressin with the non-coded amino acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), in the position 2 ([Tic2, Lys8]VP (I)) and in the position 3 ([Tic3, Lys8]VP (II)). The analogue containing only one Tic in place of both aromatic residues was also isolated (des-Tyr2-[Tic3, Lys8]VP (III)). The biological activities of all analogues were negligible.

A Rubber-Like Protein in Insect Cuticle

1960 ◽  
Vol 37 (4) ◽  
pp. 889-907 ◽  
Author(s):  
TORKEL WEIS-FOGH
Keyword(s):  
Amino Acid ◽  
Tertiary Structure ◽  
Three Dimensional ◽  
Water Soluble ◽  
Insect Cuticle ◽  
Peptide Backbone ◽  
Experimental Proof ◽  
Dimensional Network ◽  
New Type ◽  
Elastic Protein

1. A new type of hyaline, colourless cuticle, called rubber-like cuticle, is described and analysed qualitatively with respect to mechanical behaviour, structure and composition. Externally it is covered by ordinary thin epicuticle, but otherwise it represents the simplest type of cuticle known and consists only of thin continuous lamellae of chitin (0-2 µ) separated and glued together by an elastic protein, resilin, not hitherto described. There are only traces of water-soluble substances present and resilin sometimes occurs as pure, hyaline patches more than 100 µ thick and suitable for macroscopic experiments. 2. In all physical respects, resilin behaves like a swollen isotropic rubber but the rigid experimental proof is given elsewhere (Weis-Fogh, 1961). An outstanding feature is the complete lack of flow not paralleled by other natural or synthetic rubbers. 3. Resilin resembles elastin but it is devoid of colour and has a different and characteristic amino-acid composition (Bailey & Weis-Fogh, 1961). The nature of the cross-linkages is unknown at present but they are extremely stable, of a co-valent type and different from other known cross-linkages in proteins. This accounts for its insolubility and resistance to all agents which do not break the peptide backbone. 4. Resilin is a structure protein in which the primary chains show little or no tendency to form secondary structures; they are bound together in a uniform three-dimensional network (the tertiary structure) with no potential limits as to size.

scholarly journals Unbiased Identification of Immunogenic Staphylococcus aureus Leukotoxin B-Cell Epitopes

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
David N. Hernandez ◽  
Kayan Tam ◽  
Bo Shopsin ◽  
Emily E. Radke ◽  
Pegah Kolahi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Amino Acid ◽  
Phage Display ◽  
B Cell ◽  
Three Dimensional ◽  
Amino Acid Side Chain ◽  
Gene Fragment ◽  
B Cell Epitopes ◽  
Content Type ◽  
Amino Acid Peptide

ABSTRACT Unbiased identification of individual immunogenic B-cell epitopes in major antigens of a pathogen remains a technology challenge for vaccine discovery. We therefore developed a platform for rapid phage display screening of deep recombinant libraries consisting of as few as one major pathogen antigen. Using the bicomponent pore-forming leukocidin (Luk) exotoxins of the major pathogen Staphylococcus aureus as a prototype, we randomly fragmented and separately ligated the hemolysin gamma A (HlgA) and LukS genes into a custom-built phage display system, termed pComb-Opti8. Deep sequence analysis of barcoded amplimers of the HlgA and LukS gene fragment libraries demonstrated that biopannng against a cross-reactive anti-Luk monoclonal antibody (MAb) recovered convergent molecular clones with short overlapping homologous sequences. We thereby identified an 11-amino-acid sequence that is highly conserved in four Luk toxin subunits and is ubiquitous in representation within S. aureus clinical isolates. The isolated 11-amino-acid peptide probe was predicted to retain the native three-dimensional (3D) conformation seen within the Luk holotoxin. Indeed, this peptide was recognized by the selecting anti-Luk MAb, and, using mutated peptides, we showed that a particular amino acid side chain was essential for these interactions. Furthermore, murine immunization with this peptide elicited IgG responses that were highly reactive with both the autologous synthetic peptide and the full-length Luk toxin homologues. Thus, using a gene fragment- and phage display-based pipeline, we have identified and validated immunogenic B-cell epitopes that are cross-reactive between members of the pore-forming leukocidin family. This approach could be harnessed to identify novel epitopes for a much-needed S. aureus-protective subunit vaccine.

Mutational studies of protein structures and their stabilities

1992 ◽  
Vol 25 (2) ◽  
pp. 205-250 ◽  
Author(s):  
David Shortle
Keyword(s):  
Amino Acid ◽  
Functional Role ◽  
Hydrophobic Interactions ◽  
Protein Structures ◽  
Three Dimensional ◽  
Rnase A ◽  
Side Chain ◽  
Amino Acid Side Chain ◽  
X Ray Crystallography ◽  
And Function

The fundamental relationship between structure and function has served to guide investigations into the workings of living systems at all levels - from the whole organism to individual cells on down to individual molecules. When X-ray crystallography began to reveal the three-dimensional structures of proteins like myoglobin, lysozyme and RNase A, protein chemists were well prepared to draw inferences about functional mechanisms from the precise positioning of amino acid residues they could see. The close proximity between an amino acid side chain and a chemical group on a bound ligand strongly suggests a functional role for that side chain in binding affinity and specificity. Likewise, the nearly universal finding of large clusters of hydrophobic side chains buried in the core of proteins strongly supports a major functional role of hydrophobic interactions in protein folding and stability. Even though eminently plausible hypotheses like these, grounded in the most fundamental principles of chemistry and the logic of structure–function relationships, become widely accepted and make their way into textbooks, protein chemists have felt compelled to search for ways to test them and put them on a more quantitative basis.

Synthesis and properties of analogues of vasopressin with 1-aminocyclopropane-1-carboxylic acid in position 9

1988 ◽  
Vol 53 (11) ◽  
pp. 2604-2616 ◽  
Author(s):  
Zdenko Procházka ◽  
Juris E. Ancans ◽  
Jiřina Slaninová ◽  
Alena Machová ◽  
Tomislav Barth ◽  
...  
Keyword(s):  
Biological Activity ◽  
Amino Acid ◽  
Nmr Spectroscopy ◽  
Carboxylic Acid ◽  
Arginine Vasopressin ◽  
Solid Phase ◽  
Biological Activities ◽  
Solution Conformation ◽  
Lysine Vasopressin ◽  
C Nmr

Solid phase methodology on benzhydrylamine resin was used for the synthesis of three analogues of vasopressin with non-coded amino acid, 1-aminocyclopropane 1-carboxylic acid, in position 9. Two analogues of lysine-vasopressin ([Lys8, Acc9]vasopressin (I) and Gly3-[Lys8, Acc9]vasopressin (II)) and one analogue of arginine-vasopressin ([Arg8, Acc9]vasopressin (III)) have been synthesized. The dubious value of the biological activity of [Lys8, D-Ala9]vasopressin was reevaluated and [Lys8, L-Ala9]vasopressin was also synthesized and tested for the comparison. Differences in solution conformation of these two analogues were studied by 1H and 13C NMR spectroscopy. Biological activities of all analogues were either significantly lowered or almost completely eliminated. Analogues I-III were found to be completely inactive in analgesia and the CNS activities tested (active and passive avoidance).

scholarly journals Interaction of human neutrophil flavocytochrome b with cytosolic proteins: transferred-NOESY NMR studies of a gp91phox C-terminal peptide bound to p47phox

1997 ◽  
Vol 325 (1) ◽  
pp. 249-257 ◽  
Author(s):  
Earle R. ADAMS ◽  
Edward A. DRATZ ◽  
Dawit GIZACHEW ◽  
Frank R. DeLEO ◽  
Lixin YU ◽  
...  
Keyword(s):  
Amino Acid ◽  
Nadph Oxidase ◽  
Nuclear Overhauser Effect ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Side Chains ◽  
Nmr Studies ◽  
C Terminus ◽  
Amino Acid Side Chains ◽  
Flavocytochrome B

During activation of the neutrophil NADPH oxidase, cytosolic p47phox is translocated to the membrane where it associates with flavocytochrome b via multiple binding regions, including a site in the C-terminus of gp91phox. To investigate this binding site further, we studied the three-dimensional structure of a gp91phox C-terminal peptide (551SNSESGPRGVHFIFNKEN568) bound to p47phox using transferred nuclear Overhauser effect spectroscopy (Tr-NOESY) NMR. Using MARDIGRAS analysis and simulated annealing, five similar sets of structures of the p47phox-bound peptide were obtained, all containing an extended open bend from Ser5 to Phe14 (corresponding to gp91phox residues 555–564). The ends of the peptide were poorly defined, however, suggesting they were more flexible. Therefore further refinement was performed on the Ser5–Phe14 region of the peptide after omitting the ends of the peptide from consideration. In this case, two similar structures were obtained. Both structures again exhibited extended open-bend conformations. In addition, the amino acid side chains that showed evidence of immobilization on binding to p47phox correlated directly with those that were found previously to be essential for biological activity. Thus during NADPH oxidase assembly, the C-terminus of gp91phox binds to 47phox in an extended conformation between gp91phox residues 555 and 564, with immobilization of all of the amino acid side chains in the 558RGVHFIF564 region except for His561.

Tetrazoloquinolines: Synthesis, Reactions, and Applications

2020 ◽  
Vol 24 (4) ◽  
pp. 439-464 ◽  
Author(s):  
Rizk E. Khidre ◽  
Tahah A. Ameen ◽  
Mounir A. I. Salem
Keyword(s):  
Carboxylic Acid ◽  
Chemical Reactions ◽  
Sodium Azide ◽  
Biological Activities ◽  
Quinoline Derivatives ◽  
Pharmacological Activities ◽  
Synthesis Reactions ◽  
Intramolecular Cyclocondensation

This review summarizes the synthesis, reactions, and biological activities of tetrazolo[1,5-a]quinoline derivatives. These derivatives were synthesized by several methods such as i) from the reaction of 2-chloroquinoline with sodium azide ii) from diazotization 2-hydrazinylquinoline derivatives, and iii) from intramolecular cyclocondensation of 2-azidoarylidenes. Also, the chemical reactions and pharmacological activities of some tetrazoloquinolines such as tetrazolo[1,5-a]quinoline-4-carbaldehyde, 5-chlorotetrazolo[ 1,5-a]quinoline, 4-(chloromethyl)tetrazolo[1,5-a]quinoline, tetrazolo[1,5- a]quinoline-4-carboxylic acid, and 5-azidotetrazolo[1,5-a]quinoline were discussed.

Analogues of the cholecystokinin octapeptide modified in the central part of the molecule

1991 ◽  
Vol 56 (9) ◽  
pp. 1963-1970 ◽  
Author(s):  
Jan Hlaváček ◽  
Václav Čeřovský ◽  
Jana Pírková ◽  
Pavel Majer ◽  
Lenka Maletínská ◽  
...  
Keyword(s):  
Amino Acid ◽  
Biological Activities ◽  
Point Of View ◽  
Biologically Active ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Cholecystokinin Octapeptide ◽  
Biological Tests ◽  
Biological Potency ◽  
Biologically Active Conformation

In a series of analogues of the cholecystokinin octapeptide (CCK-8) the amino acid residues were gradually modified by substituting Gly by Pro in position 4, Trp by His in position 5, Met by Cle in position 6, or the Gly residue was inserted between Tyr and Met in positions 2 and 3 of the peptide chain, and in the case of the cholecystokinin heptapeptide (CCK-7) the Met residues were substituted by Nle or Aib. These peptides were investigated from the point of view of their biological potency in the peripheral and central region. From the results of the biological tests it follows that the modifications carried out in these analogues and in their Nα-Boc derivatives mean a suppression of the investigated biological activities by 2-3 orders of magnitude (at a maximum dose of the tested substance of 2 . 10-2 mg per animal).This means that a disturbance of the assumed biologically active conformation of CCK-8, connected with a considerable decrease of the biological potency of the molecule, takes place not only after introduction of the side chain into its centre (substitution of Gly4), but also after the modification of the side chains of the amino acids or by extension of the backbone in further positions around this central amino acid.

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