ABSTRACT
Selective modulation of autophagy is a promising therapeutic strategy, especially for cancer treatment. However, the lack of specific autophagy inhibitors limits this strategy. The formation of the ATG12-ATG5-ATG16L1 complex is essential for targeting the ATG12-ATG5 conjugate to proper membranes and to generate LC3-II for the progression of autophagy. Thus, targeting ATG5-ATG16L1 protein-protein interactions (PPIs) might inhibit early stage autophagy with high specificity. In this paper, we report that a stapled peptide derived from ATG16L1 exhibits potent binding affinity to ATG5, striking resistance to proteolysis, and significant autophagy inhibition activities in cells.
Subject(s)
Carrier Proteins , Microtubule-Associated Proteins , Autophagy , Autophagy-Related Protein 5/metabolism , Autophagy-Related Proteins/metabolism , Carrier Proteins/metabolism , Hydrocarbons , Microtubule-Associated Proteins/metabolism , Peptides/metabolism , Peptides/pharmacologyABSTRACT
Sacchathridine A (1) was isolated from the fermentation broth of strain Saccharothrix sp. MI559-46F5. The structure was determined as a new naphthoquinone derivative with an acetylhydrazino moiety by a combination of NMR, MS spectral analyses, and chemical degradation. Compound 1 showed inhibitory activity of prostaglandin E2 release in a concentration-dependent manner from human synovial sarcoma cells, SW982, with an IC50 value of 1.0 µM, but had no effect on cell growth up to 30 µM.
Subject(s)
Actinomycetales/chemistry , Dinoprostone/antagonists & inhibitors , Naphthoquinones/isolation & purification , Naphthoquinones/pharmacology , Prostaglandin Antagonists/isolation & purification , Prostaglandin Antagonists/pharmacology , Dinoprostone/metabolism , Dose-Response Relationship, Drug , Humans , Inhibitory Concentration 50 , Molecular Structure , Naphthoquinones/chemistry , Nuclear Magnetic Resonance, Biomolecular , Prostaglandin Antagonists/chemistry , Sarcoma, Synovial/drug therapyABSTRACT
Five human 2,3-oxidosqualnene cyclase (OSC) inhibitors were discovered using the combination of a virtual screening based on a docking study and an isotope-free assay system. All of these inhibitors were revealed to have activities comparable or superior to that of LDAO, a known OSC inhibitor. The computational study of the newly identified inhibitors suggested that CH/π interactions with F444 and W581 contribute to the binding, and these interactions are candidates for additional structural filters in the next generation of virtual screening.
Subject(s)
Chemistry, Pharmaceutical/methods , Intramolecular Transferases/antagonists & inhibitors , Catalysis , Catalytic Domain , Computer Simulation , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Isotopes/chemistry , Models, Chemical , Molecular Conformation , Risk Factors , SoftwareABSTRACT
A synthetic route to paleic acid 1, antimicrobial agent effective against Mannheimia haemolytica and Pasteurella multocida, has been established. The absolute configuration of the secondary hydroxyl group was controlled by a catalytic asymmetric alkylation of an aldehyde using a chiral titanium sulfonamide complex and the cis double bond was installed using a Wittig reaction. This synthetic route was also applied to the preparation of structurally related analogs, which were used in structure-activity relationship studies for antibacterial activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Mannheimia haemolytica/drug effects , Oleic Acids/chemical synthesis , Pasteurella multocida/drug effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Microbial Sensitivity Tests , Oleic Acids/chemistry , Oleic Acids/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Paleic acid (1), an antibiotic, was obtained from a fermentation broth of Paenibacillus sp. BMK771-AF3. The compound is a fatty acid (9Z,16R)-16-hydroxy-9-octadecenoic acid ((R)-16-hydroxyoleic acid), whose isolation required protection of its polar functional groups. Mosher esters of paleic acid yielded information on the absolute configuration of secondary alcohol, and well-resolved (1)H NMR peaks around the double bond suggested that olefin adopted a Z geometry. Paleic acid showed potent antibacterial activity and narrow spectrum against Mannheimia haemolytica with MIC values ranging between 0.78 and 1.56 microg ml(-1).
