ELIZA

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308018 occurrences (No.72 in the rank) during 5 years in the PubMed. [cache]

18) A number of GLP-1R agonists (GLP-1RAs) feature a fatty acid moiety to prolong their pharmacokinetics via increased albumin binding, but the potential for these chemical changes to influence GLP-1R function has rarely been investigated beyond potency assessments for cAMP.

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PMID:34315812 DOI:10.1124/molpharm.121.000270

2021 Molecular pharmacology

* Acylation of the Incretin Peptide Exendin-4 Directly Impacts Glucagon-Like Peptide-1 Receptor Signaling and Trafficking.

- The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor and mainstay therapeutic target for the treatment of type 2 diabetes and obesity. Recent reports have highlighted how biased agonism at the GLP-1R affects sustained glucose-stimulated insulin secretion through avoidance of desensitization and downregulation. A number of GLP-1R agonists (GLP-1RAs) feature a fatty acid moiety to prolong their pharmacokinetics via increased albumin binding, but the potential for these chemical changes to influence GLP-1R function has rarely been investigated beyond potency assessments for cAMP. Here, we directly compare the prototypical GLP-1RA exendin-4 with its C-terminally acylated analog, exendin-4-C16. We examine relative propensities of each ligand to recruit and activate G proteins and β-arrestins, endocytic and postendocytic trafficking profiles, and interactions with model and cellular membranes in HEK293 and HEK293T cells. Both ligands had similar cAMP potency, but exendin-4-C16 showed ∼2.5-fold bias toward G protein recruitment and a ∼60% reduction in β-arrestin-2 recruitment efficacy compared with exendin-4, as well as reduced GLP-1R endocytosis and preferential targeting toward recycling pathways. These effects were associated with reduced movement of the GLP-1R extracellular domain measured using a conformational biosensor approach and a ∼70% increase in insulin secretion in INS-1 832/3 cells. Interactions with plasma membrane lipids were enhanced by the acyl chain. Exendin-4-C16 showed extensive albumin binding and was highly effective for lowering of blood glucose in mice over at least 72 hours. Our study highlights the importance of a broad approach to the evaluation of GLP-1RA pharmacology. SIGNIFICANCE STATEMENT: Acylation is a common strategy to enhance the pharmacokinetics of peptide-based drugs. This work shows how acylation can also affect various other pharmacological parameters, including biased agonism, receptor trafficking, and interactions with the plasma membrane, which may be therapeutically important.

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(1)389 of	(4)10 table	(7)3 is	(10)2 Sequencing
(2)19 and	(5)5 in	(8)3 variation
(3)18 table,	(6)3 null	(9)3 variations

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--- WordNet output for number --- =>に番号をつける, 数, 番号, 総数, 若干, 多数, 曲, 過ごす, 達する, 番号を唱える Overview of noun number The noun number has 11 senses (first 9 from tagged texts) 1. (131) number, figure -- (the property possessed by a sum or total or indefinite quantity of units or individuals; "he had a number of chores to do"; "the number of parameters is small"; "the figure was about a thousand") 2. (63) number -- (a concept of quantity involving zero and units; "every number has a unique position in the sequence") 3. (5) act, routine, number, turn, bit -- (a short theatrical performance that is part of a longer program; "he did his act three times every evening"; "she had a catchy little routine"; "it was one of the best numbers he ever did") 4. (5) phone number, telephone number, number -- (the number is used in calling a particular telephone; "he has an unlisted number") 5. (2) numeral, number -- (a symbol used to represent a number; "he learned to write the numerals before he went to school") 6. (2) issue, number -- (one of a series published periodically; "she found an old issue of the magazine in her dentist's waiting room") 7. (1) number -- (a select company of people; "I hope to become one of their number before I die") 8. (1) number, identification number -- (a numeral or string of numerals that is used for identification; "she refused to give them her Social Security number") 9. (1) number -- (a clothing measurement; "a number 13 shoe") 10. number -- (the grammatical category for the forms of nouns and pronouns and verbs that are used depending on the number of entities involved (singular or dual or plural); "in English the subject and the verb must agree in number") 11. number -- (an item of merchandise offered for sale; "she preferred the black nylon number"; "this sweater is an all-wool number") Overview of verb number The verb number has 6 senses (first 3 from tagged texts) 1. (6) total, number, add up, come, amount -- (add up in number or quantity; "The bills amounted to $2,000"; "The bill came to $2,000") 2. (2) number -- (give numbers to; "You should number the pages of the thesis") 3. (1) number, list -- (enumerate; "We must number the names of the great mathematicians") 4. count, number -- (put into a group; "The academy counts several Nobel Prize winners among its members") 5. count, number, enumerate, numerate -- (determine the number or amount of; "Can you count the books on your shelf?"; "Count your change") 6. number, keep down -- (place a limit on the number of) --- WordNet end ---