1333332-17-4Relevant articles and documents
α-Conotoxin ImI incorporating stable cystathionine bridges maintains full potency and identical three-dimensional structure
Dekan, Zoltan,Vetter, Irina,Daly, Norelle L.,Craik, David J.,Lewis, Richard J.,Alewood, Paul F.
, p. 15866 - 15869 (2011)
The two disulfide bonds of α-conotoxin ImI, a peptide antagonist of the α7 nicotinic acetylcholine receptor (nAChR), were systematically replaced with isosteric redox-stable cystathionine thioethers. Regioselective thioether formation was accomplished on solid support through substitution of a γ-chlorohomoalanine by an intramolecular cysteine thiol to produce hybrid thioether/disulfide analogues (2 and 3) as well as a dual cystathionine analogue (4) that were found to be structurally homologous to α-conotoxin ImI by 1H NMR. The antagonistic activity at the α7 nAChR of cystathionine analogue 3 (pIC50 = 6.41 ± 0.09) was identical to that of α-conotoxin ImI (1, pIC50 = 6.41 ± 0.09), whereas those of 2 (pIC50 = 5.96 ± 0.09) and 4 (pIC 50 = 5.89 ± 0.09) showed a modest decrease. The effect of oxidation of the thioethers to sulfoxides was also investigated, with significant changes in the biological activities observed ranging from a >30-fold reduction (2S=O) to a 3-fold increase (3S=OB) in potencies.
Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis
Tejeda, Elizabeth J. Curiel,Bello, Angelica M.,Wasilewski, Ewa,Koebel, Adam,Dunn, Shannon,Kotra, Lakshmi P.
, p. 8876 - 8887 (2017)
Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases including multiple sclerosis. An α-amino acid-based core structure, derived from a hydantoin core, with unique heterocycles on the side chains were synthesized as potential noncovalent inhibitors of PAD enzymes. Among the various heterocycles investigated, compound 23, carrying an imidazole moiety, exhibited the highest potency in this series with some selectivity for PAD2, and was further investigated in vivo. Pharmacokinetics in mice suggested the Cmax to be 12.0 ± 2.5 μg/mL and 170 ± 10 ng/mL in the serum and brain, respectively, when compound 23 was administered at 50 mg/kg via single dose ip. At the same dose, compound 23 also reversed physical disability and cleared the brain of T-cell infiltration in an EAE mouse model of multiple sclerosis (MS). This novel series of compounds show promise for further development as disease modifying agents for the potential treatment of MS.
A one-pot chemoenzymatic synthesis of (2S, 4R)-4-methylproline enables the first total synthesis of antiviral lipopeptide cavinafungin B
Zwick, Christian R.,Renata, Hans
, p. 6469 - 6473 (2018/10/05)
We report an efficient ten-step (longest linear sequence) synthesis of antiviral natural product cavinafungin B in 37% overall yield. By leveraging a one-pot chemoenzymatic synthesis of (2S,4R)-4-methylproline and oxazolidine-tethered (AT (Boc)G-Rink resin) SPPS methodology, the assembly of our molecular target could be conducted in an efficient manner. This general strategy could prove amenable to the construction of other natural and unnatural linear lipopeptides. The value of incorporating biocatalytic steps in complex molecule synthesis is highlighted by this work.
INHIBITORS OF PEPTIDYL ARGININE DEIMINASE (PAD) ENZYMES AND USES THEREOF
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Paragraph 00138; 00141, (2017/03/14)
The present application relates to a-substituted amino acid compounds of the Formula (I), compositions comprising these compounds and their use, in particular for the treatment of diseases, disorders or conditions characterized by or associated with the hypercitrullination of proteins by peptidyl arginine deiminase (PAD) enzymes.
