Identification of Histone deacetylase (HDAC)‐Associated Proteins with DNA‐Programmed Affinity Labeling

Zhang, Chenglong; Peng, Jianzhao; Huang, Yiran; Meng, Ling; Li, Qingrong; Xiong, Feng; Li, Xiaoyü

doi:10.1002/anie.202001205

Cited by 23 publications

(18 citation statements)

References 72 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, a single BP can be paired with multiple CPs at different positions to create multiple probe configurations to maximize labeling coverage. This feature has been recently used to profile large protein complexes in cell lysates . Finally, DNA-based probes can be multiplexed to interrogate multiple proteins simultaneously.…”

Section: Discussionmentioning

confidence: 99%

Evolution of the Selection Methods of DNA-Encoded Chemical Libraries

Song

2021

Acc. Chem. Res.

Self Cite

View full text Add to dashboard Cite

Metrics & MoreArticle Recommendations * sı Supporting Information CONSPECTUS: In the past two decades, a DNA-encoded chemical library (DEL or DECL) has emerged and has become a major technology platform for ligand discovery in drug discovery as well as in chemical biology research. Although based on a simple concept, i.e., encoding each compound with a unique DNA tag in a combinatorial chemical library, DEL has been proven to be a powerful tool for interrogating biological targets by accessing vast chemical space at a fraction of the cost of traditional high-throughput screening (HTS). Moreover, the recent technological advances and rapid developments of DEL-compatible reactions have greatly enhanced the chemical diversity of DELs. Today, DELs have been adopted by nearly all major pharmaceutical companies and are also gaining momentum in academia. However, this field is heavily biased toward library encoding and synthesis, and an underexplored aspect of DEL research is the selection methods. Generally, DEL selection is considered to be a massive binding assay conducted over an immobilized protein to identify the physical binders using the typical bind−wash−elute procedure. In recent years, we and other research groups have developed new approaches that can perform DEL selections in the solution phase, which has enabled the selection against complex biological targets beyond purified proteins. On the one hand, these methods have significantly widened the target scope of DELs; on the other hand, they have enabled the functional and potentially phenotypic assays of DELs beyond simple binding. An overview of these methods is provided in this Account.Our laboratory has been using DNA-programmed affinity labeling (DPAL) as the main strategy to develop new DEL selection methods. DPAL is based on DNA-templated synthesis; by using a known ligand to guide the target binding, DPAL is able to specifically establish a stable linkage between the target protein and the ligand. The DNA tag of the target-ligand conjugates serves as a programmable handle for protein characterization or hit compound decoding in the case of DEL selections. DPAL also takes advantage of the fast reaction kinetics of photo-cross-linking to achieve high labeling specificity and fidelity, especially in the selection of DNA-encoded dynamic libraries (DEDLs). DPAL has enabled DEL selections not only in buffer and cell lysates but also with complex biological systems, such as large protein complexes and live cells. Moreover, this strategy has also been employed in other biological applications, such as site-specific protein labeling, protein detection, protein profiling, and target identification. In the Account, we describe these methods, highlight their underlying principles, and conclude with perspectives of the development of the DEL technology.

show abstract

Section: Discussionmentioning

confidence: 99%

Evolution of the Selection Methods of DNA-Encoded Chemical Libraries

Song

2021

Acc. Chem. Res.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Initially, the DNA tag was delivered using a DNA-programmed affinity labelling (DPAL) method previously developed for protein profiling and target identification. [75,88] This study showed that small molecules and antibodies could be used for tag delivery. Other types of ligands that have been used to graft DNAs on cells, such as peptides, [89] small-engineered proteins, [90] and aptamers, [91] may also be used to expand the target scope.…”

Section: Selection Against Membrane Proteinsmentioning

confidence: 95%

“…Recently, Li and co-workers reported a DNAprogrammed affinity labelling (DPAL) of histone deacetylase (HDAC) complexes, suggesting the possibility of DEL selection against endogenous protein complexes in cell lysates without purification and immobilization. [75]…”

Section: Selection In Cell Lysates and With Protein Complexesmentioning

confidence: 99%

“…Some protein complexes are quite stable and, although with no reported examples, should be tractable to immobilization and affinity‐based selection. Recently, Li and co‐workers reported a DNA‐programmed affinity labelling (DPAL) of histone deacetylase (HDAC) complexes, suggesting the possibility of DEL selection against endogenous protein complexes in cell lysates without purification and immobilization [75] …”

Section: Selections With Complex Biological Targetsmentioning

confidence: 99%

“…The method was tested with three membrane proteins: folate receptor (FR), carbonic anhydrase 12 (CA‐12), and epidermal growth factor receptor (EGFR), and novel nanomolar to low micromolar binders have been identified. Initially, the DNA tag was delivered using a DNA‐programmed affinity labelling (DPAL) method previously developed for protein profiling and target identification [75,88] . This study showed that small molecules and antibodies could be used for tag delivery.…”

Section: Selections With Complex Biological Targetsmentioning

confidence: 99%

See 2 more Smart Citations

Recent Advances on the Selection Methods of DNA‐Encoded Libraries

Huang

2021

ChemBioChem

Self Cite

View full text Add to dashboard Cite

DNA-encoded libraries (DEL) have come of age and become a major technology platform for ligand discovery in both academia and the pharmaceutical industry. Technological maturation in the past two decades and the recent explosive developments of DEL-compatible chemistries have greatly improved the chemical diversity of DELs and fueled its applications in drug discovery. A relatively less-covered aspect of DELs is the selection method. Typically, DEL selection is considered as a binding assay and the selection is conducted with purified protein targets immobilized on a matrix, and the binders are separated from the non-binding background via physical washes. However, the recent innovations in DEL selection methods have not only expanded the target scope of DELs, but also revealed the potential of the DEL technology as a powerful tool in exploring fundamental biology. In this Review, we first cover the "classic" DEL selection methods with purified proteins on solid phase, and then we discuss the strategies to realize DEL selections in solution phase. Finally, we focus on the emerging approaches for DELs to interrogate complex biological targets.

show abstract

Selection Strategies in DNA-Encoded Libraries

Gui

2022

Topics in Medicinal Chemistry

View full text Add to dashboard Cite

Identification of Histone deacetylase (HDAC)‐Associated Proteins with DNA‐Programmed Affinity Labeling

Cited by 23 publications

References 72 publications

Evolution of the Selection Methods of DNA-Encoded Chemical Libraries

Evolution of the Selection Methods of DNA-Encoded Chemical Libraries

Recent Advances on the Selection Methods of DNA‐Encoded Libraries

Selection Strategies in DNA-Encoded Libraries

Contact Info

Product

Resources

About