Small, but powerful and attractive: 19F in biomolecular NMR

Gronenborn, Angela M.

doi:10.1016/j.str.2021.09.009

Cited by 59 publications

(42 citation statements)

References 101 publications

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“…Of particular importance, the differences in the biomechanical properties of the IVD are likely to result predominantly from the IVD structural organization rather than compositional variation [ 106 ]. Structural and biomechanical studies have shown that elastic fibers contribute significantly to the structure and function of IVDs; however, more studies using advanced technologies are required to fully characterize their mechanical properties, including in health and disease conditions [ 107 , 108 , 109 , 110 ]. While recent studies have identified that elastic fiber breakdown products, such as elastokines, play a role in the development of a variety of diseases, i.e., supravalvular aortic stenosis and the Williams-Beuren syndrome, the impact of the process on IVD pathologies is yet unclear [ 111 , 112 ].…”

Section: Future Outlookmentioning

confidence: 99%

Elastic Fibers in the Intervertebral Disc: From Form to Function and toward Regeneration

Cyril

Giugni

Bangar

et al. 2022

IJMS

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Despite extensive efforts over the past 40 years, there is still a significant gap in knowledge of the characteristics of elastic fibers in the intervertebral disc (IVD). More studies are required to clarify the potential contribution of elastic fibers to the IVD (healthy and diseased) function and recommend critical areas for future investigations. On the other hand, current IVD in-vitro models are not true reflections of the complex biological IVD tissue and the role of elastic fibers has often been ignored in developing relevant tissue-engineered scaffolds and realistic computational models. This has affected the progress of IVD studies (tissue engineering solutions, biomechanics, fundamental biology) and translation into clinical practice. Motivated by the current gap, the current review paper presents a comprehensive study (from the early 1980s to 2022) that explores the current understanding of structural (multi-scale hierarchy), biological (development and aging, elastin content, and cell-fiber interaction), and biomechanical properties of the IVD elastic fibers, and provides new insights into future investigations in this domain.

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Section: Future Outlookmentioning

confidence: 99%

Elastic Fibers in the Intervertebral Disc: From Form to Function and toward Regeneration

Cyril

Giugni

Bangar

et al. 2022

IJMS

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“…Towards understanding the rate of unmasking inside the live cells, we developed an in-cell time-resolved 19 F-NMR to monitor the rate of POM group unmasking (Figure 6). 19 F-NMR is uniquely suited for this task due to the high receptivity of 19 F, low background in biological samples and remarkable sensitivity of 19 F chemical shifts to their chemical environment [53][54] . The latter means that even the distant fluorine of MN551 could act as a reporter for the presence of the masking group on the phosphotyrosine moiety.…”

Section: Scheme 5 Synthesis Of Mn551 Prodrugsmentioning

confidence: 99%

Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2

Ramachandran

Makukhin

Haubrich

et al. 2022

Preprint

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The Src homology 2 (SH2) domain is present in many proteins that bind to phosphotyrosine (pY) post translational modifications in partner proteins to trigger downstream signalling. Since pY-driven protein-protein interactions can sustain disease, SH2 domains have long been the focus of small-molecule ligand discovery efforts, but have been stymied by the poor drug-like properties of phosphate and its mimetics. Here, we have used structure-based design to target the SH2 domain of the suppressor of cytokine signalling 2 (SOCS2) – the substrate recognition subunit of a Cullin5 RING E3 ligase. Starting from the highly ligand-efficient pY amino acid, a fragment growing approach improved binding affinities in the nanomolar range. During the course optimization campaign, in one of our co-crystal structures we observed serendipitous modification of Cys111 at a flexible variable loop distal from the phosphate binding site. This inspired the rational design of a cysteine-directed electrophilic covalent inhibitor MN551. A prodrug strategy using a pivaloyloxymethyl (POM) protecting group aided cell permeability and its rapid unmasking inside the cell enabled efficient and selective covalent engagement of SOCS2. We qualify MN551 and its masked analogue MN714 as covalent inhibitors of SOCS2, that could find attractive applications as chemical probes to understand the biology of SOCS2 and its CRL5 complex, and as covalent E3 ligase handles in proteolysis targeting chimera (PROTACs) to induce targeted protein degradation. More broadly, this work provides a blueprint for developing and exploiting pY-based small molecules to target other SH2 domains.

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“…19 F NMR screening, one of the available biophysical tools, [1–3] is a highly effective and well‐established hit‐finding approach [4–10] . The ligand‐observed 19 F NMR screening method known as FAXS (Fluorine chemical shift Anisotropy and eXchange for Screening) can be performed in a direct or competition mode and allows the measurement of the binding affinity of the identified hits [4] .…”

Section: Introductionmentioning

confidence: 99%

Efficient Screening of Target‐Specific Selected Compounds in Mixtures by ¹⁹F NMR Binding Assay with Predicted ¹⁹F NMR Chemical Shifts

et al. 2022

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Ligand-based 19 F NMR screening is a highly effective and wellestablished hit-finding approach. The high sensitivity to protein binding makes it particularly suitable for fragment screening. Different criteria can be considered for generating fluorinated fragment libraries. One common strategy is to assemble a large, diverse, well-designed and characterized fragment library which is screened in mixtures, generated based on experimental 19 F NMR chemical shifts. Here, we introduce a complementary knowledge-based 19 F NMR screening approach, named 19 Fo-cused screening, enabling the efficient screening of putative active molecules selected by computational hit finding methodologies, in mixtures assembled and on-the-fly deconvoluted based on predicted 19 F NMR chemical shifts. In this study, we developed a novel approach, named LEFshift, for 19 F NMR chemical shift prediction using rooted topological fluorine torsion fingerprints in combination with a random forest machine learning method. A demonstration of this approach to a real test case is reported.

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Small, but powerful and attractive: 19F in biomolecular NMR

Cited by 59 publications

References 101 publications

Elastic Fibers in the Intervertebral Disc: From Form to Function and toward Regeneration

Elastic Fibers in the Intervertebral Disc: From Form to Function and toward Regeneration

Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2

Efficient Screening of Target‐Specific Selected Compounds in Mixtures by ¹⁹F NMR Binding Assay with Predicted ¹⁹F NMR Chemical Shifts

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Small, but powerful and attractive: 19F in biomolecular NMR

Cited by 59 publications

References 101 publications

Elastic Fibers in the Intervertebral Disc: From Form to Function and toward Regeneration

Elastic Fibers in the Intervertebral Disc: From Form to Function and toward Regeneration

Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2

Efficient Screening of Target‐Specific Selected Compounds in Mixtures by 19F NMR Binding Assay with Predicted 19F NMR Chemical Shifts

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Efficient Screening of Target‐Specific Selected Compounds in Mixtures by ¹⁹F NMR Binding Assay with Predicted ¹⁹F NMR Chemical Shifts