A Conformationally Constrained Vasopressin Analog with Antidiuretic Antagonistic Activity

Skala, Gerald; Smith, Clark W.; Taylor, Catherine; Ludens, James H.

doi:10.1126/science.6541806

Cited by 19 publications

(5 citation statements)

References 23 publications

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“…[51] Other turn mimetics for GPCR targets include agonists (45-52) of melanocortin, bradykinin, casmorphin, endothelin, enkephalin, GHRP-2, gonadotrophin releasing hormone, oxytocin and vasopressin ( Figure 9). [52][53][54][55][56][57] Aside from GPCRs, constrained cyclic peptides have been developed to mimic turns from many other protein and peptides. This includes the integrins, which are an important class of surface receptors involved in cell-cell and cell-matrix interactions.…”

Section: Cyclic Peptide Turnsmentioning

confidence: 99%

Constraining Cyclic Peptides To Mimic Protein Structure Motifs

et al. 2014

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Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well-defined three-dimensional structures. Short synthetic peptide sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable protein-like structures in water. However, short peptides can be induced to fold into protein-like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine-tune three-dimensional structure. Such constrained cyclic peptides can have protein-like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three-dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic peptides and synthetic macrocyclic peptidomimetics that refine peptide structure and confer biological properties.

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Section: Cyclic Peptide Turnsmentioning

confidence: 99%

Constraining Cyclic Peptides To Mimic Protein Structure Motifs

et al. 2014

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“…Most of the retromodified peptides, with the exception of 3-6 and 8, are potent Vz antagonists with anti-Vz pAz values in the range 7.24 (10) to 8.10 (24 and 25). Virtually all of the retromodified peptides, with the exceptions of 5 and 6, are also potent Via antagonists, with anti-Via pA2 values in the range 7.30 (24) to 8.27 (22). In a number of instances the retromodified peptides exhibited significant enhancement in anti-Vz potency relative to the parent Eda peptide.…”

Section: Resultsmentioning

confidence: 96%

“…With only one exception (peptide 8), the retromodified peptides exhibit either full retention and in a number of cases (2, 7, 9-12,14, and 16) a 1.5-7.5-fold enhancement of V2 antagonism compared to their respective parent C-terminal Eda peptides. The retro-Arg-substituted lie4 peptide 22 exhibits a 2-fold enhancement of anti-V2 potency relative to its Val4 counterpart 18. The retromodified peptides 24 and 25, which possess extensions at the C-terminal, also exhibit good retention of V2 antagonism.…”

mentioning

confidence: 99%

Potent V2/V1a vasopressin antagonists with C-terminal ethylenediamine-linked retro-amino acids

Manning

Przybylski²,

Grzonka³

et al. 1992

J. Med. Chem.

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We report the solid-phase synthesis and antagonistic potencies of 25 analogues (1-25) of [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O-ethyl-D-tyrosine,4-valine]arginine-vasopressin (d(CH2)5D-Tyr(Et)2-VAVP) (A) and of the related Ile4 (D) and [D-Phe2,Ile4] (E) analogues, potent antagonists of the antidiuretic (V2-receptor) and of the vasopressor (V1a-receptor) responses to arginine-vasopressin (AVP). Six of these peptides (1, 13, 17, 19, 21, and 23) have the Pro-Arg-Gly-NH2 tripeptide side chain fully or partially replaced or extended by ethylenediamine (Eda). The remaining 19 peptides have L- or D-amino acids retrolinked to these six C-terminal Eda peptides. Peptides 1, 13, 17, and 19 all have the ring structure of (A). Their side-chain structures are as follows: 1, Eda; 13, Pro-Eda; 17, Pro-Arg-Eda; 19, Arg-Gly-Eda. Peptide 21 is the Pro-Arg-Eda analogue of D; peptide 23 is the Pro-Arg-Gly-Eda analogue of E. Peptide 2 is the retro-Arg analogue of 1. Its side-chain structure is Eda<--Arg. Peptides 3-6 are analogues of 2 which have the D-Tyr-(Et)2 residue replaced by L-Tyr(Et)2 (3), D-Phe2 (4), D-Ile2 (5), or D-Leu2 (6), respectively. Peptides 7-12 are analogues of 2 which have the C-terminal retro-Arg replaced in retrofashion by D-Arg (7), Gly (8), Orn (9), D-Orn (10), D-Lys (11), or Arg-Arg (12). Peptides 14-16 have D-Orn (14), D-Lys (15), and D-Arg (16) retrosubstituted to peptide 13. Peptides 18, 20, and 22 are the retro-Arg-substituted analogues of 17, 19, and 21, respectively. Peptides 24 and 25 have Val and D-Val in retrolinkage with 23, respectively. All 25 peptides were examined for agonistic and antagonistic potencies in AVP V2/V1a assays. With the exception of peptides 5 and 6, all exhibit potent anti-V1a antagonism, with anti-V1a pA2 values in the range 7.64-8.33.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Among the conformations of the presented peptides, the lowest energy conformer of [BPhe 3 ]AVP obtained with X-PLOR reveals a similar backbone and side-chain conformation of Gln 4 to the crystal structure of pressinoic acid. Furthermore, the Asn 5 side-chain lies over the molecule as in the case of pressinoic acid, in contrast to the Asn 5 in vasopressin which extends away from the cyclic part of the peptide (Skala et al, 1984).…”

Section: Resultsmentioning

confidence: 99%

Solution structure of conformationally restricted vasopressin analogues.

Trzepałka¹,

Oleszczuk²,

Maciejczyk³

et al. 2004

Acta Biochim Pol

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In recent years, a massive effort has been directed towards designing potent and selective antagonists of neurohypophyseal hormones substituted at position 3. Modification of vasopressin at position 3 with 4,4'-biphenylalanine results in pharmacologically inactive analogues. Chemically, this substitution appears to vary only slightly from those previously made by us (1-Nal or 2-Nal), which afforded potent agonists of V(2) receptors. In this situation, it seemed worthwhile to study the structure of the analogues with 4,4'-biphenylalanine (BPhe) at position 3 in aqueous solution using NMR spectroscopy and total conformational analysis. This contribution is part of extensive studies aimed at understanding spatial structures of 3-substituted [Arg(8)]vasopressin analogues of different pharmacological properties. NMR data were used to calculate 3D structures for all the analogues using two methods, EDMC with the ECEPP/3 force field, and molecular dynamic with the simulated annealing (SA) algorithm. The structures obtained by the first method show a better fit between the NMR spectral evidence and the calculation for all the peptides.

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A Conformationally Constrained Vasopressin Analog with Antidiuretic Antagonistic Activity

Cited by 19 publications

References 23 publications

Constraining Cyclic Peptides To Mimic Protein Structure Motifs

Constraining Cyclic Peptides To Mimic Protein Structure Motifs

Potent V2/V1a vasopressin antagonists with C-terminal ethylenediamine-linked retro-amino acids

Solution structure of conformationally restricted vasopressin analogues.

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