pHLIP-FIRE, a cell insertion-triggered fluorescent probe for imaging tumors demonstrates targeted cargo delivery in vivo.

Abstract:

:We have developed an improved tool for imaging acidic tumors by reporting the insertion of a transmembrane helix: the pHLIP-Fluorescence Insertion REporter (pHLIP-FIRE). In acidic tissues, such as tumors, peptides in the pHLIP family insert as α-helices across cell membranes. The cell-inserting end of the pHLIP-FIRE peptide has a fluorophore-fluorophore or fluorophore-quencher pair. A pair member is released by disulfide cleavage after insertion into the reducing environment inside a cell, resulting in dequenching of the probe. Thus, the fluorescence of the pHLIP-FIRE probe is enhanced upon cell-insertion in the targeted tissues but is suppressed elsewhere due to quenching. Targeting studies in mice bearing breast tumors show strong signaling by pHLIP-FIRE, with a contrast index of ∼17, demonstrating (i) direct imaging of pHLIP insertion and (ii) cargo translocation in vivo. Imaging and targeted cargo delivery should each have clinical applications.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Karabadzhak AG,An M,Yao L,Langenbacher R,Moshnikova A,Adochite RC,Andreev OA,Reshetnyak YK,Engelman DM

doi

10.1021/cb500388m

subject

Has Abstract

pub_date

2014-11-21 00:00:00

pages

2545-53

issue

11

eissn

1554-8929

issn

1554-8937

journal_volume

9

pub_type

杂志文章
  • HIV-1 Env-Dependent Cell Killing by Bifunctional Small-Molecule/Peptide Conjugates.

    abstract::A strategy has been established for the synthesis of a family of bifunctional HIV-1 inhibitor covalent conjugates with the potential to bind simultaneously to both the gp120 and gp41 subunits of the HIV-1 envelope glycoprotein trimeric complex (Env). One component of the conjugates is derived from BNM-III-170, a small...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.0c00888

    authors: Gaffney A,Nangarlia A,Ang CG,Gossert S,Rashad Ahmed AA,Hossain MA,Abrams CF,Smith AB 3rd,Chaiken I

    更新日期:2021-01-15 00:00:00

  • Diverse functional roles of reactive cysteines.

    abstract::Cysteine residues on proteins play key roles in catalysis and regulation. These functional cysteines serve as active sites for nucleophilic and redox catalysis, sites of allosteric regulation, and metal-binding ligands on proteins from diverse classes including proteases, kinases, metabolic enzymes, and transcription ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章,评审

    doi:10.1021/cb3005269

    authors: Pace NJ,Weerapana E

    更新日期:2013-02-15 00:00:00

  • Chemical modification of conotoxins to improve stability and activity.

    abstract::Conotoxins are small disulfide-rich peptides from the venom of cone snails. Along with other conopeptides, they target a wide range of membrane receptors, ion channels, and transporters, and because of their high potency and selectivity for defined subtypes of these receptors, they have attracted a great deal of atten...

    journal_title:ACS chemical biology

    pub_type: 杂志文章,评审

    doi:10.1021/cb700091j

    authors: Craik DJ,Adams DJ

    更新日期:2007-07-20 00:00:00

  • Covalent Modifiers of Botulinum Neurotoxin Counteract Toxin Persistence.

    abstract::Botulinum neurotoxins (BoNTs) are the most potent toxins known to man and a significant threat as weapons of bioterrorism. BoNTs contain a metalloprotease domain that blocks neurotransmitter release in nerve terminals, resulting in a descending, flaccid paralysis with a 5-10% mortality rate. Existing treatment options...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.8b00937

    authors: Garland M,Babin BM,Miyashita SI,Loscher S,Shen Y,Dong M,Bogyo M

    更新日期:2019-01-18 00:00:00

  • Design and characterization of an active site selective caspase-3 transnitrosating agent.

    abstract::The oxidative addition of nitric oxide (NO) to a thiol, S-nitrosation, is a focus of studies on cyclic guanosine monophosphate (cGMP)-independent NO signaling. S-Nitrosation of the catalytic cysteine of the caspase proteases has important effects on apoptosis and consequently has received attention. Here we report on ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb600393x

    authors: Mitchell DA,Morton SU,Marletta MA

    更新日期:2006-11-21 00:00:00

  • Mechanistic Insights into Taxadiene Epoxidation by Taxadiene-5α-Hydroxylase.

    abstract::The anticancer molecule taxol (Paclitaxel) stands as one of the most medically and economically important natural products. However, despite decades of extensive study, its biosynthesis remains poorly understood. Unpredictable behavior of the first oxygenation enzyme, taxadiene-5α-hydroxylase, which produces a range o...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.5b00767

    authors: Edgar S,Zhou K,Qiao K,King JR,Simpson JH,Stephanopoulos G

    更新日期:2016-02-19 00:00:00

  • Mutations of Triad Determinants Changes the Substrate Alignment at the Catalytic Center of Human ALOX5.

    abstract::For the specificity of ALOX15 orthologs of different mammals, the geometry of the amino acids Phe353, Ile418, Met419, and Ile593 ("triad determinants") is important, and mutagenesis of these residues altered the reaction specificity of these enzymes. Here we expressed wild-type human ALOX5 and its F359W/A424I/N425M/A6...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.9b00674

    authors: Ivanov I,Golovanov AB,Ferretti C,Canyelles-Niño M,Heydeck D,Stehling S,Lluch JM,González-Lafont À,Kühn H

    更新日期:2019-12-20 00:00:00

  • Residue-Based Preorganization of BH3-Derived α/β-Peptides: Modulating Affinity, Selectivity and Proteolytic Susceptibility in α-Helix Mimics.

    abstract::We report progress toward a general strategy for mimicking the recognition properties of specific α-helices within natural proteins through the use of oligomers that are less susceptible than conventional peptides to proteolysis. The oligomers contain both α- and β-amino acid residues, with the density of the β subuni...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.5b00109

    authors: Peterson-Kaufman KJ,Haase HS,Boersma MD,Lee EF,Fairlie WD,Gellman SH

    更新日期:2015-07-17 00:00:00

  • MARCKS-ED peptide as a curvature and lipid sensor.

    abstract::Membrane curvature and lipid composition regulates important biological processes within a cell. Currently, several proteins have been reported to sense and/or induce membrane curvatures, e.g., Synaptotagmin-1 and Amphiphysin. However, the large protein scaffold of these curvature sensors limits their applications in ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb300429e

    authors: Morton LA,Yang H,Saludes JP,Fiorini Z,Beninson L,Chapman ER,Fleshner M,Xue D,Yin H

    更新日期:2013-01-18 00:00:00

  • Multiple Chemical Inducible Tal Effectors for Genome Editing and Transcription Activation.

    abstract::Inducible modulation is often required for precise investigations and manipulations of dynamic biological processes. Transcription activator-like effectors (TALEs) provide a powerful tool for targeted gene editing and transcriptional programming. We designed a series of chemical inducible systems by coupling TALEs wit...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.7b00606

    authors: Zhao C,Zhang Y,Zhao Y,Ying Y,Ai R,Zhang J,Wang Y

    更新日期:2018-03-16 00:00:00

  • Reaction mechanism of N-acetylneuraminic acid lyase revealed by a combination of crystallography, QM/MM simulation, and mutagenesis.

    abstract::N-Acetylneuraminic acid lyase (NAL) is a Class I aldolase that catalyzes the reversible condensation of pyruvate with N-acetyl-d-mannosamine (ManNAc) to yield the sialic acid N-acetylneuraminic acid (Neu5Ac). Aldolases are finding increasing use as biocatalysts for the stereospecific synthesis of complex molecules. In...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb500067z

    authors: Daniels AD,Campeotto I,van der Kamp MW,Bolt AH,Trinh CH,Phillips SE,Pearson AR,Nelson A,Mulholland AJ,Berry A

    更新日期:2014-04-18 00:00:00

  • Stepwise Loop Insertion Strategy for Active Site Remodeling to Generate Novel Enzyme Functions.

    abstract::The remodeling of active sites to generate novel biocatalysts is an attractive and challenging task. We developed a stepwise loop insertion strategy (StLois), in which randomized residue pairs are inserted into active site loops. The phosphotriesterase-like lactonase from Geobacillus kaustophilus (GkaP-PLL) was used t...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.7b00018

    authors: Hoque MA,Zhang Y,Chen L,Yang G,Khatun MA,Chen H,Hao L,Feng Y

    更新日期:2017-05-19 00:00:00

  • Traceless labeling of glycoproteins and its application to the study of glycoprotein-protein interactions.

    abstract::A new chemical method for the traceless labeling of glycoproteins with synthetic boronic acid (BA)-tosyl probes was successfully developed. The BA moiety acts as an affinity head to direct the formation of a cyclic boronate diester with the diol groups of glycans. Following this step, the electrophilic tosyl group is ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb400631w

    authors: Yang YL,Lee YP,Yang YL,Lin PC

    更新日期:2014-02-21 00:00:00

  • An Isotope-Coded Photocleavable Probe for Quantitative Profiling of Protein O-GlcNAcylation.

    abstract::O-linked N-acetylglucosamine ( O-GlcNAc) is a ubiquitous post-translational modification of proteins and is essential for cell function. Quantifying the dynamics of O-GlcNAcylation in a proteome-wide level is critical for uncovering cellular mechanisms and functional roles of O-GlcNAcylation in cells. Here, we develop...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.8b01052

    authors: Li J,Li Z,Duan X,Qin K,Dang L,Sun S,Cai L,Hsieh-Wilson LC,Wu L,Yi W

    更新日期:2019-01-18 00:00:00

  • Precursor-Guided Mining of Marine Sponge Metabolomes Lends Insight into Biosynthesis of Pyrrole-Imidazole Alkaloids.

    abstract::Pyrrole-imidazole alkaloids are natural products isolated from marine sponges, holobiont metazoans that are associated with symbiotic microbiomes. Pyrrole-imidazole alkaloids have attracted attention due to their chemical complexity and their favorable pharmacological properties. However, insights into how these molec...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.0c00375

    authors: Mohanty I,Moore SG,Yi D,Biggs JS,Gaul DA,Garg N,Agarwal V

    更新日期:2020-08-21 00:00:00

  • Detecting Secretory Proteins by Acoustic Droplet Ejection in Multiplexed High-Throughput Applications.

    abstract::Nearly one-third of the encoded proteome is comprised of secretory proteins that enable communication between cells and organ systems, playing a ubiquitous role in human health and disease. High-throughput detection of secreted proteins would enhance efforts to identify therapies for secretion-related diseases. Using ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.9b00001

    authors: Iannotti MJ,MacArthur R,Jones R,Tao D,Singeç I,Michael S,Inglese J

    更新日期:2019-03-15 00:00:00

  • Directed Evolution Reveals the Functional Sequence Space of an Adenylation Domain Specificity Code.

    abstract::Nonribosomal peptides are important natural products biosynthesized by nonribosomal peptide synthetases (NRPSs). Adenylation (A) domains of NRPSs are highly specific for the substrate they recognize. This recognition is determined by 10 residues in the substrate-binding pocket, termed the specificity code. This findin...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.9b00532

    authors: Throckmorton K,Vinnik V,Chowdhury R,Cook T,Chevrette MG,Maranas C,Pfleger B,Thomas MG

    更新日期:2019-09-20 00:00:00

  • A molecular-beacon-based screen for small molecule inhibitors of miRNA maturation.

    abstract::miRNAs are small non-coding RNAs that regulate about 60% of mammalian genes by modulating their transcript levels. Network scale studies of miRNA-mediated regulatory circuits demonstrate the central importance of this class of small RNA in the maintenance of biological robustness. More recently, several reports have d...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb300650y

    authors: Bose D,Jayaraj GG,Kumar S,Maiti S

    更新日期:2013-05-17 00:00:00

  • The Role of Reactive Oxygen Species and Ferroptosis in Heme-Mediated Activation of Human Platelets.

    abstract::Hemolysis, a process by which the destruction of red blood cells leads to the release of hemoglobin, is a critical event observed during hemolytic disorders. Under oxidative stress conditions, hemoglobin can release its heme prosthetic group, which is highly cytotoxic and can catalyze the generation of reactive oxygen...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.8b00458

    authors: NaveenKumar SK,SharathBabu BN,Hemshekhar M,Kemparaju K,Girish KS,Mugesh G

    更新日期:2018-08-17 00:00:00

  • Ebselen: Mechanisms of Glutamate Dehydrogenase and Glutaminase Enzyme Inhibition.

    abstract::Ebselen modulates target proteins through redox reactions with selenocysteine/cysteine residues, or through binding to the zinc finger domains. However, a recent contradiction in ebselen inhibition of kidney type glutaminase (KGA) stimulated our interest in investigating its inhibition mechanism with glutamate dehydro...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.7b00728

    authors: Yu Y,Jin Y,Zhou J,Ruan H,Zhao H,Lu S,Zhang Y,Li D,Ji X,Ruan BH

    更新日期:2017-12-15 00:00:00

  • Cruentaren A binds F1F0 ATP synthase to modulate the Hsp90 protein folding machinery.

    abstract::The molecular chaperone Hsp90 requires the assistance of immunophilins, co-chaperones, and partner proteins for the conformational maturation of client proteins. Hsp90 inhibition represents a promising anticancer strategy due to the dependence of numerous oncogenic signaling pathways upon Hsp90 function. Historically,...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb400906e

    authors: Hall JA,Kusuma BR,Brandt GE,Blagg BS

    更新日期:2014-04-18 00:00:00

  • Using self-assembled monolayers to understand α8β1-mediated cell adhesion to RGD and FEI motifs in nephronectin.

    abstract::Nephronectin is an extracellular matrix protein that interacts with the α8β1 integrin receptor and plays a role in tissue and organ development, though the motifs that mediate adhesion to the receptor remain unclear. This paper describes the use of self-assembled monolayers to study the adhesion of α8β1-presenting cel...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb200186j

    authors: Sánchez-Cortés J,Mrksich M

    更新日期:2011-10-21 00:00:00

  • Boron dipyrromethene as a fluorescent caging group for single-photon uncaging with long-wavelength visible light.

    abstract::Caged compounds are useful tools for precise spatiotemporal modulation of cell functions, but in most cases uncaging requires ultraviolet (UV) light, which is cytotoxic and has limited tissue penetration. Therefore, caged compounds that can be activated by longer-wavelength light are required. Here we describe a novel...

    journal_title:ACS chemical biology

    pub_type: 信件

    doi:10.1021/cb500525p

    authors: Umeda N,Takahashi H,Kamiya M,Ueno T,Komatsu T,Terai T,Hanaoka K,Nagano T,Urano Y

    更新日期:2014-10-17 00:00:00

  • Novel modifications in RNA.

    abstract::The past several years have seen numerous reports of new chemical modifications for use in RNA. In addition, in that time period, we have seen the discovery of several previously unknown naturally occurring modifications that impart novel properties on the parent RNAs. In this review, we describe recent discoveries in...

    journal_title:ACS chemical biology

    pub_type: 杂志文章,评审

    doi:10.1021/cb200422t

    authors: Phelps K,Morris A,Beal PA

    更新日期:2012-01-20 00:00:00

  • A derivatized scorpion toxin reveals the functional output of heteromeric KCNQ1-KCNE K+ channel complexes.

    abstract::KCNE transmembrane peptides are a family of modulatory beta-subunits that assemble with voltage-gated K+ channels, producing the diversity of potassium currents needed for proper function in a variety of tissues. Although all five KCNE transcripts have been found in cardiac and other tissues, it is unclear whether two...

    journal_title:ACS chemical biology

    pub_type: 信件

    doi:10.1021/cb700089s

    authors: Morin TJ,Kobertz WR

    更新日期:2007-07-20 00:00:00

  • Humanized Lewis-Y specific antibody based delivery of STAT3 siRNA.

    abstract::The clinical application of siRNA is limited largely by the lack of efficient, cell-specific delivery systems. Antibodies are attractive delivery vehicles for targeted therapy due to their high specificity. In this study we describe the use of a humanized monoclonal antibody (mAb), hu3S193, against Lewis-Y (Le(y)), as...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb200176v

    authors: Ma Y,Kowolik CM,Swiderski PM,Kortylewski M,Yu H,Horne DA,Jove R,Caballero OL,Simpson AJ,Lee FT,Pillay V,Scott AM

    更新日期:2011-09-16 00:00:00

  • Heavy Metals Induce Decline of Derivatives of 5-Methycytosine in Both DNA and RNA of Stem Cells.

    abstract::Toxic heavy metals have been considered to be harmful environmental contaminations. The molecular mechanisms of heavy-metals-induced cytotoxicity and carcinogenicity are still not well elucidated. Previous reports showed exposures to toxic heavy metals can cause a change of DNA cytosine methylation (5-methylcytosine, ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.7b00170

    authors: Xiong J,Liu X,Cheng QY,Xiao S,Xia LX,Yuan BF,Feng YQ

    更新日期:2017-06-16 00:00:00

  • Protein Modification by Endogenously Generated Lipid Electrophiles: Mitochondria as the Source and Target.

    abstract::Determining the impact of lipid electrophile-mediated protein damage that occurs during oxidative stress requires a comprehensive analysis of electrophile targets adducted under pathophysiological conditions. Incorporation of ω-alkynyl linoleic acid into the phospholipids of macrophages prior to activation by Kdo2-lip...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.7b00480

    authors: Beavers WN,Rose KL,Galligan JJ,Mitchener MM,Rouzer CA,Tallman KA,Lamberson CR,Wang X,Hill S,Ivanova PT,Brown HA,Zhang B,Porter NA,Marnett LJ

    更新日期:2017-08-18 00:00:00

  • Exploiting structural analysis, in silico screening, and serendipity to identify novel inhibitors of drug-resistant falciparum malaria.

    abstract::Plasmodium falciparum thymidylate synthase-dihydrofolate reductase (TS-DHFR) is an essential enzyme in folate biosynthesis and a major malarial drug target. This bifunctional enzyme thus presents different design approaches for developing novel inhibitors against drug-resistant mutants. We performed a high-throughput ...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/cb8002804

    authors: Dasgupta T,Chitnumsub P,Kamchonwongpaisan S,Maneeruttanarungroj C,Nichols SE,Lyons TM,Tirado-Rives J,Jorgensen WL,Yuthavong Y,Anderson KS

    更新日期:2009-01-16 00:00:00

  • Chemical Tools for Selective Activity Profiling of Endogenously Expressed MMP-14 in Multicellular Models.

    abstract::Matrix metalloproteases (MMPs) are a large family of zinc-dependent endopeptidases involved in a diverse set of physiological and pathological processes, most notably in cancer. Current methods for imaging and quantifying MMP activity lack sufficient selectivity and spatiotemporal resolution to allow studies of specif...

    journal_title:ACS chemical biology

    pub_type: 杂志文章

    doi:10.1021/acschembio.8b00562

    authors: Amara N,Tholen M,Bogyo M

    更新日期:2018-09-21 00:00:00