دورية أكاديمية
أعرض في EDS

Enzymatic Macrolactamization of mRNA Display Libraries for Inhibitor Selection.

التفاصيل البيبلوغرافية
العنوان: Enzymatic Macrolactamization of mRNA Display Libraries for Inhibitor Selection.
المؤلفون: Bowler MM; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Glavatskikh M; Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Pecot CV; UNC Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Kireev D; Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Bowers AA; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
المصدر: ACS chemical biology [ACS Chem Biol] 2023 Jan 20; Vol. 18 (1), pp. 166-175. Date of Electronic Publication: 2022 Dec 09.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101282906 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8937 (Electronic) Linking ISSN: 15548929 NLM ISO Abbreviation: ACS Chem Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society, c2006-
مواضيع طبية MeSH: Peptide Library* , Proteins*/metabolism, RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Ligands ; Protein Binding ; Transglutaminases/genetics ; Transglutaminases/chemistry ; Transglutaminases/metabolism
مستخلص: mRNA display is a powerful, high-throughput technology for discovering novel, peptide ligands for protein targets. A number of methods have been used to expand the chemical diversity of mRNA display libraries beyond the 20 canonical amino acids, including genetic code reprogramming and biorthogonal chemistries. To date, however, there have been few reports using enzymes as biocompatible reagents for diversifying mRNA display libraries. Here, we report the evaluation and implementation of the common industrial enzyme, microbial transglutaminase (mTG), as a versatile biocatalyst for cyclization of mRNA display peptide libraries via lysine-to-glutamine isopeptide bonds. We establish two separate display-based assays to validate the compatibility of mTG with mRNA-linked peptide substrates. These assays indicate that mTG has a high degree of substrate tolerance and low single round bias. To demonstrate the potential benefits of mTG-mediated cyclization in ligand discovery, high diversity mTG-modified libraries were employed in two separate affinity selections: (1) one against the calcium and integrin binding protein, CIB1, and (2) the second against the immune checkpoint protein and emerging therapeutic target, B7-H3. Both selections resulted in the identification of potent, cyclic, low nanomolar binders, and subsequent structure-activity studies demonstrate the importance of the cyclization to the observed activity. Notably, cyclization in the CIB1 binder stabilizes an α-helical conformation, while the B7-H3 inhibitor employs two bridges, one mTG-derived lactam and a second disulfide to achieve its potency. Together, these results demonstrate potential benefits of enzyme-based biocatalysts in mRNA display ligand selections and establish a framework for employing mTG in mRNA display.
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معلومات مُعتمدة: R35 GM125005 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (RNA, Messenger)
0 (Ligands)
0 (Peptide Library)
0 (Proteins)
EC 2.3.2.13 (Transglutaminases)
تواريخ الأحداث: Date Created: 20221209 Date Completed: 20230123 Latest Revision: 20240911
رمز التحديث: 20240911
مُعرف محوري في PubMed: PMC9868075
DOI: 10.1021/acschembio.2c00828
PMID: 36490372
قاعدة البيانات: MEDLINE
الوصف
تدمد:1554-8937
DOI:10.1021/acschembio.2c00828