Conformational analysis of cyclic analogues of theSaccharomyces cerevisiae α-factor pheromone

Antohi, Octavian; Marepalli, Hanumantha Rao; Yang, Wei; Becker, Jeffrey M.; Naider, Fred

doi:10.1002/(sici)1097-0282(199801)45:1<21::aid-bip3>3.0.co;2-0

Cited by 10 publications

(8 citation statements)

References 21 publications

(10 reference statements)

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“…Subsequently, cyclic lactam with different ring size, 16,17 cyclic disulfide, 18,19 and cyclic γ-lactam 20 were designed to induce a more favorable turn structure for the pheromone. However, such cyclization approaches to conformational rigidification generally reduce potency by 5% to 25% regardless of the adopted cyclic structures.…”

Section: 16mentioning

confidence: 99%

“…However, such cyclization approaches to conformational rigidification generally reduce potency by 5% to 25% regardless of the adopted cyclic structures. 16,17 Among the many synthetic β-turn peptidomimetics restricted by cyclization, (R)-γ-lactam conformational constraint incorporating [3-(R)-amino-2-oxo-1-pyrrolidineacetamido] in place of ProGly at residues 8 and 9 was reported to have the best activity only equal to that of parent peptide, [Nle ing approach involving the photoactivatable groups attached to the α-factor backbone was developed. 28,30,44,[51][52][53]55,56 pBenzoyl-L-phenylalanine (Bpa) and 3,4-Dihydroxyphenylalanine (DOPA) was reported to have a desirable property for this purpose, although incorporation of these groups at various positions in α-factor have been shown to result in a less than 30-fold decrease in receptor affinity.…”

Section: 16mentioning

confidence: 99%

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Highly Active Analogs of α-Factor and Their Activities Against Saccharomyces cerevisiae

Ahn¹,

Hong²,

Jin³

et al. 2014

Bulletin of the Korean Chemical Society

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Thirteen analogs of tridecapeptide α-factor (WHWLQLKPGQPMY) of Saccharomyces cerevisiae with C-or N-terminal Trp extension and isosteric replacement by Aib at position 8 and 11, Trp at position 13, D-Ala at position 9, and Orn and Glu at position 6 were synthesized and assayed for their biological activity. Receptor binding assay was carried out using our newly developed spectrophotometric method with detector peptide 14. C-or N-terminal extended analogs, α-factor-[Trp] n (n =1-5) 1-5 and [N-Trp] 1 -α-factor 6, were all less active than native α-factor and gradual decreases in both activity and receptor affinity were observed with greater Trp extension. Trp-substituted analog at position 13, [Trp 13 ]α-factor 7, exhibited about 2-fold reductions in both activity and receptor affinity. Aib-substituted analogs, [Aib 8 ]α-factor 8 and [Aib 11]α-factor 9, showed 5-to 10-fold reduction in activity as well as 3-fold reduction in receptor affinity compared to native α-factor. [Orn 6]α-factor 10 demonstrated strong potency with a 7.0-fold increase in halo activity as well as 1.8-fold increase in receptor affinity compared to native α-factor. ]α-factor 11 exhibited 15-fold higher halo activity as well as nearly 3-fold higher receptor affinity compared to native α-factor.

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Section: 16mentioning

confidence: 99%

Section: 16mentioning

confidence: 99%

Highly Active Analogs of α-Factor and Their Activities Against Saccharomyces cerevisiae

Ahn¹,

Hong²,

Jin³

et al. 2014

Bulletin of the Korean Chemical Society

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“…The largest ring constraint, from a (Lys, Glu) bridge, resulted in a flexible structure with no strong structural preference. Some of these bridged tetrapeptides have been incorporated into yeast α‐factor and examined for their solution conformations in DMSO‐ d 6 , and their effects on the biological activities of the pheromone in aqueous media 84. Interestingly, the conformational preferences observed for the tetrapeptides alone were apparently retained in the context of the full‐length pheromone.…”

Section: Conformational Control Of Peptides Using Side‐chain Lactam Bmentioning

confidence: 99%

“…In their studies of the yeast α‐factor mating pheromone, for example, Naider and colleagues were guided in their placement of a side‐chain lactam bridge constraint by the hypothesis that the Pro8–Gly9 sequence in this peptide would direct a β‐turn in the bioactive state of this 13‐residue peptide. However, after a preliminary search for turn stabilizing ( i , i + 3) bridges,83 as described above, the lactam‐constrained analogs were found to have lost considerable receptor binding potency, indicating that the conformational constraints were inappropriate for constraint of the bioactive conformation, or the bridges interfered with receptor recognition 84…”

Section: Functional Activities Of Peptides Investigated Using Side‐chmentioning

confidence: 99%

The synthesis and study of side‐chain lactam‐bridged peptides

2002

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Side-chain lactam bridges linking amino acid residues that are spaced several residues apart in the linear sequence offer a convenient and flexible method for introducing conformational constraints into a peptide structure. The availability of a variety of selectively cleavable protecting groups for amines and carboxylic acids allows for several approaches to the synthesis of monocyclic, dicyclic, and bicyclic lactam-bridged peptides by solid-phase methods. Multicyclic structures are also accessible, but segment-condensation syntheses with solution-phase cyclizations are most likely to provide the best synthetic approach to these more complex constrained peptides. Lactam bridges linking (i, i + 3)-, (i, i + 4), and (i, i + 7)-spaced residue pairs have all proven useful for stabilization of alpha helices, and (i, i + 3)-linked residues have also been demonstrated to stabilize beta-turns. These structures are finding an increasing number of applications in protein biology, including studies of protein folding, protein aggregation, peptide ligand-receptor recognition, and the development of more potent peptide therapeutics. Defining the functional roles of the amphiphilic alpha-helices in medium-sized peptide hormones, and studying helix propagation from rigid, alpha-helix initiating bicyclic peptides are among the most exciting developments currently underway in this field.

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“…Moreover, this sodium ion acted as a fixed charge site and directed a charge‐remote, sequence‐specific fragmentation of the ring‐opened peptide. Since many synthetic peptides are acetylated at the N ‐terminus25 and lactam bridges are a common link for cyclized peptides,26–31 our findings may serve as a new way of sequencing cyclic peptides containing a lactam bridge based on charge‐remote fragmentation.…”

Section: Introductionmentioning

confidence: 92%

Sequencing cyclic peptide inhibitors of mammalian ribonucleotide reductase by electrospray ionization mass spectrometry

et al. 2001

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Mammalian ribonucleotide reductase (mRR) is a potential target for cancer intervention. A series of lactam-bridged cyclic peptide inhibitors (1-9) of mRR have been synthesized and tested in previous work. These inhibitors consist of cyclic and linear regions, causing their mass spectral characterization to be a challenge. We determined the fragmentation mechanism of cyclic peptides 1-9 using an ion-trap mass spectrometer equipped with an ESI source. Low-energy collision-induced dissociation of sodiated cyclic peptides containing linear branches follows a general pathway. Fragmentation of the linear peptide region produced mainly a and b ions. The ring peptide region was more stable and ring opening required higher collision energy, mainly occurring at the amide bond adjacent to the lactam bridge. The sodium ion, which bound to the carbonyl oxygen of the lactam bridge, acted as a fixed charge site and directed a charge-remote, sequence-specific fragmentation of the ring-opened peptide. Amino acid residues were cleaved sequentially from the C-terminus to the N-terminus. Our findings have established a new way to sequence cyclic peptides containing a lactam bridge based on charge-remote fragmentation. This methodology will permit unambiguous identification of high-affinity ligands within cyclic peptide libraries.

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Conformational analysis of cyclic analogues of theSaccharomyces cerevisiae α-factor pheromone

Cited by 10 publications

References 21 publications

Highly Active Analogs of α-Factor and Their Activities Against Saccharomyces cerevisiae

Highly Active Analogs of α-Factor and Their Activities Against Saccharomyces cerevisiae

The synthesis and study of side‐chain lactam‐bridged peptides

Sequencing cyclic peptide inhibitors of mammalian ribonucleotide reductase by electrospray ionization mass spectrometry

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