Departments of Therapeutic Discovery, ‡Neuroscience, and §Pharmacokinetics & Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Published: March 2015
AI Article Synopsis
Article Abstract
NaV1.7 is a voltage-gated sodium ion channel implicated by human genetic evidence as a therapeutic target for the treatment of pain. Screening fractionated venom from the tarantula Grammostola porteri led to the identification of a 34-residue peptide, termed GpTx-1, with potent activity on NaV1.7 (IC50 = 10 nM) and promising selectivity against key NaV subtypes (20× and 1000× over NaV1.4 and NaV1.5, respectively). NMR structural analysis of the chemically synthesized three disulfide peptide was consistent with an inhibitory cystine knot motif. Alanine scanning of GpTx-1 revealed that residues Trp(29), Lys(31), and Phe(34) near the C-terminus are critical for potent NaV1.7 antagonist activity. Substitution of Ala for Phe at position 5 conferred 300-fold selectivity against NaV1.4. A structure-guided campaign afforded additive improvements in potency and NaV subtype selectivity, culminating in the design of [Ala5,Phe6,Leu26,Arg28]GpTx-1 with a NaV1.7 IC50 value of 1.6 nM and >1000× selectivity against NaV1.4 and NaV1.5.
In the present investigation, 13% ± 0.84 of the extracted and purified phycocyanin from Phormidium versicolor was obtained, with a purity of 0.69 following dialysis.
1,2,3-triazole-based ring connected with pyridazine, triazine, methyl pyrazole, diphenyl pyrazole, and pthalimide moieties through propylene linker have been synthesized for antidiabetic evaluation via click chemistry. The antidiabetic evaluations have been done by molecular docking studies and in- vitro tests and against the DPP-4 enzyme. The molecular docking studies have revealed that compounds 22, 23, 29, and 30 showed hydrogen bond with the DPP-4 enzyme while in vitro tests has revealed the compound 30 has (IC50 values 12.
Currently non-protein amino acids and synthetic peptides are widely used as blocks in drug design. Many proteases are of great interest for pharmacology due to their key role in various pathologies. Bacterial collagenase (EC 3.
Medicinal mushroom extracts, i.e. their dried biomass, have long been known as sources of bioactive compounds with positive effects on the human health.
Laboratory of Pharmacology of Natural and Synthetic Products, Institute of Biological Sciences, Federal University of Goiás, Campus Samambaia, Goiânia, Brazil.
Compound (4-(3,5-di-tert-butyl-4-hydroxybenzylamine)benzenesulfonamide) (LQFM275) was designed and synthesized from darbufelone and sulfanilamide as a new multi-target for the treatment of inflammatory diseases. LQFM275 showed a great range of safe cytotoxicity profile (100-400 μM) evaluated by MTT assay, preventing damage induced by lipopolysaccharide (LPS) in EA.hy926 cell line.
