2265-22-7Relevant academic research and scientific papers
Discovery and Characterization of a Peptide That Enhances Endosomal Escape of Delivered Proteins in Vitro and in Vivo
Li, Margie,Tao, Yong,Shu, Yilai,LaRochelle, Jonathan R.,Steinauer, Angela,Thompson, David,Schepartz, Alanna,Chen, Zheng-Yi,Liu, David R.
, p. 14084 - 14093 (2015)
The inefficient delivery of proteins into mammalian cells remains a major barrier to realizing the therapeutic potential of many proteins. We and others have previously shown that superpositively charged proteins are efficiently endocytosed and can bring associated proteins and nucleic acids into cells. The vast majority of cargo delivered in this manner, however, remains in endosomes and does not reach the cytosol. In this study we designed and implemented a screen to discover peptides that enhance the endosomal escape of proteins fused to superpositively charged GFP (+36 GFP). From a screen of peptides previously reported to disrupt microbial membranes without known mammalian cell toxicity, we discovered a 13-residue peptide, aurein 1.2, that substantially increases cytosolic protein delivery by up to ～5-fold in a cytosolic fractionation assay in cultured cells. Four additional independent assays for nonendosomal protein delivery collectively suggest that aurein 1.2 enhances endosomal escape of associated endocytosed protein cargo. Structure-function studies clarified peptide sequence and protein conjugation requirements for endosomal escape activity. When applied to the in vivo delivery of +36 GFP-Cre recombinase fusions into the inner ear of live mice, fusion with aurein 1.2 dramatically increased nonendosomal Cre recombinase delivery potency, resulting in up to 100% recombined inner hair cells and 96% recombined outer hair cells, compared to 0-4% recombined hair cells from +36-GFP-Cre without aurein 1.2. Collectively, these findings describe a genetically encodable, endosome escape-enhancing peptide that can substantially increase the cytoplasmic delivery of cationic proteins in vitro and in vivo.
Steroidal C-21 mercapto derivatives as dissociated steroids: Discovery of an inhaled dissociated steroid
Biju, Purakkattle,McCormick, Kevin,Aslanian, Robert,Berlin, Michael,Solomon, Daniel,Chapman, Richard,McLeod, Robbie,Prelusky, Daniel,Eckel, Stephen,Kelly, George,Natiello, Michelle,House, Aileen,Fernandez, Xiomara,Bitar, Rema,Phillips, Jonathan,Anthes, John
, p. 6343 - 6347 (2011)
A series of C-21 mercapto derivatives of hydrocortisone have been synthesized and evaluated in cell based transrepression and transactivation assays. The benzothiazole derivative, compound 6 not only showed a dissociated profile in vitro functional assays but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis) while maintaining efficacy against pulmonary inflammation and lung function.
CONJUGATES OF CARTILAGE-HOMING PEPTIDES
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Paragraph 0370; 0372, (2019/11/12)
Compositions such as pharmaceutical compositions and uses for peptide-drug conjugates are disclosed. Such compositions can deliver a drug, a peptide, or a conjugate thereof to a target region, tissue, structure or cell in cartilage.
STEROIDS AND PROTEIN-CONJUGATES THEREOF
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Paragraph 0828-0830; 0835-0838, (2018/05/27)
Described herein protein steroid conjugates that are useful, for example, for the target-specific delivery of glucocorticoids (GCs) to cells.
METHODS FOR EFFICIENT DELIVERY OF THERAPEUTIC MOLECULES IN VITRO AND IN VIVO
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Page/Page column 86, (2016/05/19)
Compositions are described for direct protein delivery into multiple cell types in the mammalian inner ear. The compositions are used to deliver protein(s) (such as gene editing factors) editing of genetic mutations associated with deafness or associated disorders thereof. The delivery of genome editing proteins for gene editing and correction of genetic mutations protect or restore hearing from genetic deafness. Methods of treatment include the intracellular delivery of these molecules to a specific therapeutic target.
SELECTIVE GLUCOCORTICOID RECEPTOR LIGANDS
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Page/Page column 34; 54; 55, (2015/06/03)
Described herein are certain steroid derivative compounds, for example of formula (I): wherein X1, X2, X3 L, and Ar are as defined herein, pharmaceutical compositions comprising such compounds, the use of such compounds and compositions to specifically target glucocorticoid action, and the use of such compounds and compositions in the treatment of acute and chronic inflammatory conditions, in particular rheumatoid arthritis, haematological and other malignancies, and for causing immunosuppression in the prevention or treatment of transplant rejection, as well as methods of preparing such compounds.
Synthesis of new local anti-inflammatory thiosteroids based on antedrug concept
Milioni, C,Jung, L,Koch, B
, p. 947 - 951 (2007/10/02)
The synthesis and the in vitro pharmacological evaluation of a number of topical corticosteroid derivatives designed on the basis of the antedrug concept are reported.Three series of compounds were synthesized in which sulfur-containing amino acids were incorporated to the steroidal structure in the 21 position.Compounds of series I are diesters of cystine with the 21-hydroxyl groups of the corticosteroids, while series II and III contain 21-amino and 21-thio corticosteroid derivatives, respectively.The new compounds were less potent than the parent corticosteroidsin vitro.The 21-yl--S-acetylamino cysteine 13 was the most interesting compound of the series and is now under further evaluation. topical anti-inflammatory steroids / sulfur amino acids / corticosteroid activity
Affinity-Labelling Corticoids I. Synthesis of 21-Chloroprogesterone, Deoxycorticosterone 21-(1-Imidazole) Carboxylate, 21-Deoxy-21-Chloro Dexamethasone, and Dexamethasone 21-Mesylate, 21-Bromoacetate, and 21-Iodoacetate
Dunkerton, Lois V.,Markland, Francis S.,Li, Ming P.
, p. 1 - 6 (2007/10/02)
The efficient and unambiguous preparation of several C-21 substituted affinity-labelling corticoids are described.Included is an improved procedure for the preparation of 21-chloroprogesterone and the first reported synthesis of deoxycorticosterone 21-(1-imidazole) carboxylate.Dexamethasone derivatives prepared include seperate and unambiguous synthesis of 21-deoxy-21-chlorodexamethasone and dexamethasone 21-mesylate, as well as the first reported synthesis of dexamethasone 21-bromoacetate and dexamethasone 21-iodoacetate.
α-Keto Mesylate: A Reactive, Thiol-Specific Functional Group
Simons, Stoney S.,Pons, Michel,Johnson, David F.
, p. 3084 - 3088 (2007/10/02)
A systematic study of the reactivity of α-keto mesylates with various nucleophiles (i.e., carboxylate, -OH, imidazole, -NH2, thiol acid anion, and -SH) under mildly basic conditions is reported. α-Keto mesylates do not react with imidazole or hydroxyl groups, react extremely slowly (if at all) with carboxylate and primary amines, and react several thousand times faster with thiols and thiol acid anions.The very rapid reaction with thiols occurs only with the dissociated thiolate anion.The addition of a β-hydroxyl group to α-keto mesylates accelerates the reaction with thiolate anions by a factor of 3-12 in acetone but has no effect on reactions run in dimethylformamide. α-Keto mesylates exhibit the same selectivity for thiolate anions, as compared to amines, as do α-keto chlorides.In view of this reactivity and selectivity, the α-keto mesylate appears to be a promising functional group for the electrophilic affinity labeling of biological macromolecules in weakly basic solutions.
