DNA-encoded chemical library(DEL)represents an emerging drug discovery technology to construct com-pound libraries with abundant chemical combinations.While drug-like small molecule DELs facilitate the discovery of bi...DNA-encoded chemical library(DEL)represents an emerging drug discovery technology to construct com-pound libraries with abundant chemical combinations.While drug-like small molecule DELs facilitate the discovery of binders against targets with defined pockets,macrocyclic DELs harboring extended scaffolds enable targeting of the protein–protein interaction(PPI)interface.We previously demonstrated the design of the first-generation DNA-encoded multiple display based on a constant macrocyclic scaffold,which harvested binders against difficult targets such as tumor necrosis factor-α(TNF-α).Here,we developed a novel strategy which utilized four orthogonal amine-protecting groups on DNA,to explore larger chem-ical combinations on the same constant macrocyclic scaffold,following the parallel paradigm to mimic the versatile antibody-like multivalent epitope recognition patterns.We successfully integrated these or-thogonal protecting groups with acylation and made a mock second-generation DNA-encoded display combination.This work illustrates a strategy to produce larger encoded multiple display on a constant macrocyclic scaffold,which could facilitate potential binder discovery with enhanced affinity to clinically significant PPI targets.展开更多
DNA-encoded chemical libraries technology has become a novel approach to finding hit compounds in early drug discovery.The chemical space in a DEL would be expanded to realize its full potential,especially when integr...DNA-encoded chemical libraries technology has become a novel approach to finding hit compounds in early drug discovery.The chemical space in a DEL would be expanded to realize its full potential,especially when integrating privileged scaffold dihydroquinazoline that has demonstrated a variety of diverse bioactivities.Driven by the requirement of parallel combinatorial synthesis,we here report a facile synthesis of on-DNA dihydroquinazolinone from aldehyde and anthranilamide.This DNA-compatible reaction was promoted by antimony trichloride,which has been proven to accelerate the reaction and improve conversions.Notably,the broad substrate scope of aldehydes and anthranilamides was explored under the mild reaction condition to achieve moderate-to-excellent conversion yields.We further applied the reaction into on-DNA macrocyclization,obtaining macrocycles embedded dihydroquinazolinone scaffold in synthetically useful conversion yields.展开更多
DNA-encoded chemical library(DEL)links the power of amplifiable genetics and the nonself-replicating chemical phenotypes,generating a diverse chemical world.In analogy with the biological world,the DEL world can evolv...DNA-encoded chemical library(DEL)links the power of amplifiable genetics and the nonself-replicating chemical phenotypes,generating a diverse chemical world.In analogy with the biological world,the DEL world can evolve by using a chemical central dogma,wherein DNA replicates using the PCR reactions to amplify the genetic codes,DNA sequencing transcripts the genetic information,and DNA-compatible synthesis translates into chemical phenotypes.Importantly,DNA-compatible synthesis is the key to expanding the DEL chemical space.Besides,the evolution-driven selection system pushes the chemicals to evolve under the selective pressure,i.e.,desired selection strategies.In this perspective,we summarized recent advances in expanding DEL synthetic toolbox and panning strategies,which will shed light on the drug discovery harnessing in vitro evolution of chemicals via DEL.展开更多
Solid bubbles have expanded the SERS assay toolbox,but their detection performance in biofluids is still hampered by the irrational design of the plasmonic sensing interface.A plasmonic bubble aggregate-driven DNA-enc...Solid bubbles have expanded the SERS assay toolbox,but their detection performance in biofluids is still hampered by the irrational design of the plasmonic sensing interface.A plasmonic bubble aggregate-driven DNA-encoded SERS assay is reported here that enables simultaneous,ultrasensitive,and specific detection of multiple miRNAs in blood samples for accurate cancer diagnosis.In this assay,the buoyancy of plasmonic bubbles allows them to self-aggregate at a droplet apex for SERS reconfiguration,form single-layer bubble aggregates with plasmonic nanogaps,and prevent the coffee ring effect during evaporation assembly.Furthermore,DNA-encoded plasmonic bubbles seamlessly couple with dual-color catalytic hybridization assembly to amplify the specific miRNA-responsive Raman signal,and function as both an analyte concentrator and a Raman signal aggregator without external forces.Using these merits,this magnet-free,portable assay achieves femtomolar dual-miRNA quantitation with single-base resolution,simultaneous miRNA detection across four cell lines,and accurate cancer diagnosis(AUC=1)via analyzing 40 blood samples with machine learning,thus providing a promising tool for clinical diagnosis.展开更多
Drug discovery is a sophisticated process that incorporates scientific innovations and cuttingedge technologies.Compared to traditional bioactivity-based screening methods,encoding and display technologies for combina...Drug discovery is a sophisticated process that incorporates scientific innovations and cuttingedge technologies.Compared to traditional bioactivity-based screening methods,encoding and display technologies for combinatorial libraries have recently advanced from proof-of-principle experiments to promising tools for pharmaceutical hit discovery due to their high screening efficiency,throughput,and resource minimization.This review systematically summarizes the development history,typology,and prospective applications of encoding and displayed technologies,including phage display,ribosomal display,mRNA display,yeast cell display,one-bead one-compound,DNA-encoded,peptide nucleic acidencoded,and new peptide-encoded technologies,and examples of preclinical and clinical translation.We discuss the progress of novel targeted therapeutic agents,covering a spectrum from small-molecule inhibitors and nonpeptidic macrocycles to linear,monocyclic,and bicyclic peptides,in addition to antibodies.We also address the pending challenges and future prospects of drug discovery,including the size of screening libraries,advantages and disadvantages of the technology,clinical translational potential,and market space.This review is intended to establish a comprehensive high-throughput drug discovery strategy for scientific researchers and clinical drug developers.展开更多
基金supported by the grants from the National Natu-ral Science Foundation of China(No.21907011)the Fundamental Research Funds for the Central Universities(Nos.2020CQJQY-Z002,2021CDJYGRH-002,China)+1 种基金the Natural Science Foundation of Chongqing(No.cstc2020jcyj-jqX0009,China)the China Post-doctoral Science Foundation(No.2020M683251).
文摘DNA-encoded chemical library(DEL)represents an emerging drug discovery technology to construct com-pound libraries with abundant chemical combinations.While drug-like small molecule DELs facilitate the discovery of binders against targets with defined pockets,macrocyclic DELs harboring extended scaffolds enable targeting of the protein–protein interaction(PPI)interface.We previously demonstrated the design of the first-generation DNA-encoded multiple display based on a constant macrocyclic scaffold,which harvested binders against difficult targets such as tumor necrosis factor-α(TNF-α).Here,we developed a novel strategy which utilized four orthogonal amine-protecting groups on DNA,to explore larger chem-ical combinations on the same constant macrocyclic scaffold,following the parallel paradigm to mimic the versatile antibody-like multivalent epitope recognition patterns.We successfully integrated these or-thogonal protecting groups with acylation and made a mock second-generation DNA-encoded display combination.This work illustrates a strategy to produce larger encoded multiple display on a constant macrocyclic scaffold,which could facilitate potential binder discovery with enhanced affinity to clinically significant PPI targets.
基金supported by grants from the National Natural Science Foundation of China(Nos.22222702,22107016,22107017 and 21907011)the Fundamental Research Funds for the Central Universities(No.2022CDJQY-001)+3 种基金Beijing National Laboratory for Molecular Sciences(No.BNLMS202104)the Natural Science Foundation of Chongqing(Nos.cstc2020jcyj-jqX0009,cstc2021jcyjmsxmX0016 and cstc2021jcyj-cxttX0002)High-end Foreign Expert Introduction Program(No.G2022165020L)Shenzhen Innovation Center for Small Molecule Drug Discovery Co.(No.H20220687).
文摘DNA-encoded chemical libraries technology has become a novel approach to finding hit compounds in early drug discovery.The chemical space in a DEL would be expanded to realize its full potential,especially when integrating privileged scaffold dihydroquinazoline that has demonstrated a variety of diverse bioactivities.Driven by the requirement of parallel combinatorial synthesis,we here report a facile synthesis of on-DNA dihydroquinazolinone from aldehyde and anthranilamide.This DNA-compatible reaction was promoted by antimony trichloride,which has been proven to accelerate the reaction and improve conversions.Notably,the broad substrate scope of aldehydes and anthranilamides was explored under the mild reaction condition to achieve moderate-to-excellent conversion yields.We further applied the reaction into on-DNA macrocyclization,obtaining macrocycles embedded dihydroquinazolinone scaffold in synthetically useful conversion yields.
基金Financial support was provided by the National Natural Science Foundation of China(grant numbers 22177073,21977070,21907085,and U19A2011)the Natural Science Foundation of Shanghai,China(grant numbers 21ZR1442900 and 23ZR1437600)+2 种基金the Natural Science Foundation of Zhejiang Province,China(grant number LY22H300001)Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal SystemShanghai Key Laboratory of Orthopedic Implants(grant number KFKT202207,China)for financial support.
文摘DNA-encoded chemical library(DEL)links the power of amplifiable genetics and the nonself-replicating chemical phenotypes,generating a diverse chemical world.In analogy with the biological world,the DEL world can evolve by using a chemical central dogma,wherein DNA replicates using the PCR reactions to amplify the genetic codes,DNA sequencing transcripts the genetic information,and DNA-compatible synthesis translates into chemical phenotypes.Importantly,DNA-compatible synthesis is the key to expanding the DEL chemical space.Besides,the evolution-driven selection system pushes the chemicals to evolve under the selective pressure,i.e.,desired selection strategies.In this perspective,we summarized recent advances in expanding DEL synthetic toolbox and panning strategies,which will shed light on the drug discovery harnessing in vitro evolution of chemicals via DEL.
基金National Natural Science Foundation of China,Grant/Award Numbers:21974037,22264007,22104020Natural Science Foundation of Guangxi,Grant/Award Numbers:2021GXNSFFA220003,2022GXNSFDA035072,Guike-AD23026133+2 种基金Guangxi Science and Technology Major Program,Grant/Award Number:Guike-AA24011005Innovation Project of Guangxi Graduate Education,Grant/Award Numbers:YCBZ2023105,YCBZ2024135Guangxi Medical University Training Program for Distinguished Young Scholars。
文摘Solid bubbles have expanded the SERS assay toolbox,but their detection performance in biofluids is still hampered by the irrational design of the plasmonic sensing interface.A plasmonic bubble aggregate-driven DNA-encoded SERS assay is reported here that enables simultaneous,ultrasensitive,and specific detection of multiple miRNAs in blood samples for accurate cancer diagnosis.In this assay,the buoyancy of plasmonic bubbles allows them to self-aggregate at a droplet apex for SERS reconfiguration,form single-layer bubble aggregates with plasmonic nanogaps,and prevent the coffee ring effect during evaporation assembly.Furthermore,DNA-encoded plasmonic bubbles seamlessly couple with dual-color catalytic hybridization assembly to amplify the specific miRNA-responsive Raman signal,and function as both an analyte concentrator and a Raman signal aggregator without external forces.Using these merits,this magnet-free,portable assay achieves femtomolar dual-miRNA quantitation with single-base resolution,simultaneous miRNA detection across four cell lines,and accurate cancer diagnosis(AUC=1)via analyzing 40 blood samples with machine learning,thus providing a promising tool for clinical diagnosis.
基金supported by the National Natural Science Foundation of China(82304698 and 32300317)Science and Technology Development Fund,Macao SAR(file nos.0048/2023/ITP2,0150/2022/A3,001/2023/ALC,0006/2020/AKP and 005/2023/SKL,China)+3 种基金Guangdong Basic and Applied Basic Research Foundation(grant nos 2021A1515110338,China)Natural Science Foundation of Guangdong Province(2024A1515012659 and 2023B1515120023,China)Shenzhen-Hong Kong-Macao S&T Program(Category C)(SGDX2020110309420200,China)the Research Fund of University of Macao(CPG2024-00038-ICMS,China).
文摘Drug discovery is a sophisticated process that incorporates scientific innovations and cuttingedge technologies.Compared to traditional bioactivity-based screening methods,encoding and display technologies for combinatorial libraries have recently advanced from proof-of-principle experiments to promising tools for pharmaceutical hit discovery due to their high screening efficiency,throughput,and resource minimization.This review systematically summarizes the development history,typology,and prospective applications of encoding and displayed technologies,including phage display,ribosomal display,mRNA display,yeast cell display,one-bead one-compound,DNA-encoded,peptide nucleic acidencoded,and new peptide-encoded technologies,and examples of preclinical and clinical translation.We discuss the progress of novel targeted therapeutic agents,covering a spectrum from small-molecule inhibitors and nonpeptidic macrocycles to linear,monocyclic,and bicyclic peptides,in addition to antibodies.We also address the pending challenges and future prospects of drug discovery,including the size of screening libraries,advantages and disadvantages of the technology,clinical translational potential,and market space.This review is intended to establish a comprehensive high-throughput drug discovery strategy for scientific researchers and clinical drug developers.
