The “One-Bead-One-Compound” Combinatorial Library Method

Lam, Kit S.; Lebl, and Michal; Krchňák, Viktor

doi:10.1021/cr9600114

Cited by 751 publications

(538 citation statements)

References 338 publications

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“…high-throughput screening ͉ in vivo imaging ͉ microPET ͉ radiolabeled peptides ͉ positron emission tomography C ombinatorial chemistry (1,2) and phage display (3) techniques have become essential tools for the production of large compound libraries, which can be rapidly produced for the discovery of new drugs. Designing and implementing high-throughput screening (HTS) approaches to identify lead compounds that show affinity for a biological target from these large libraries, wherein millions of new compounds may exist, is often accomplished through in vitro screening.…”

mentioning

confidence: 99%

High-throughput in vivo screening of targeted molecular imaging agents

Gagnon¹,

Hausner²,

Mařı́k³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The rapid development and translation of targeted molecular imaging agents from bench to bedside is currently a slow process, with a clear bottleneck between the discovery of new compounds and the development of an appropriate molecular imaging agent. The ability to identify promising new molecular imaging agents, as well as failures, much earlier in the development process using high-throughput screening techniques could save significant time and money. This work combines the advantages of combinatorial chemistry, sitespecific solid-phase radiolabeling, and in vivo imaging for the rapid screening of molecular imaging agents. A one-bead-one-compound library was prepared and evaluated in vitro, leading to the identification of 42 promising lead peptides. Over 11 consecutive days, these peptides, along with a control peptide, were successfully radiolabeled with 4-[ 18 F]fluorobenzoic acid and evaluated in vivo using microPET. Four peptides were radiolabeled per day, followed by simultaneous injection of each individual peptide into 2 animals. As a result, 4 promising new molecular imaging agents were identified that otherwise would not have been selected based solely on in vitro data. This study is the first example of the practical application of a high-throughput screening approach using microPET imaging of [ 18 F]-labeled peptides for the rapid in vivo identification of potential new molecular imaging agents.high-throughput screening ͉ in vivo imaging ͉ microPET ͉ radiolabeled peptides ͉ positron emission tomography C ombinatorial chemistry (1, 2) and phage display (3) techniques have become essential tools for the production of large compound libraries, which can be rapidly produced for the discovery of new drugs. Designing and implementing high-throughput screening (HTS) approaches to identify lead compounds that show affinity for a biological target from these large libraries, wherein millions of new compounds may exist, is often accomplished through in vitro screening. In general, the 2 approaches by which this can be accomplished are either solution-phase screening techniques (4-11), generally used by drug discovery programs, or solid-phase screening, which has garnered interest for the evaluation of libraries prepared using combinatorial chemistry.Though there are many reports outlining high-throughput approaches for in vitro screening, few exist where the sole purpose is to develop high-throughput in vivo methodologies for the identification of new molecular imaging agents. While the feasibility of using magnetic resonance imaging (MRI) for high-throughput applications has been explored with both the development of scanner technology and the scanning of multiple animals in parallel (12)(13)(14)(15)(16)(17)(18)(19)(20), positron emission tomography (PET) has received very little attention for high-throughput applications. This is likely the result of the unique set of problems that arise when considering using the latter imaging modality. The half-lives of the radioactive isotopes commonly used for PET ar...

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mentioning

confidence: 99%

High-throughput in vivo screening of targeted molecular imaging agents

Gagnon¹,

Hausner²,

Mařı́k³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…A combinatorial peptide macro array interaction assay [10,[26][27][28][29] with a suckerin-peptide based library was designed in order to obtain a preliminary screening of peptide interactions and to identify binding interactions of binary peptide combinations ( Figure 1B, details of the assay are described in Materials and methods section). All binary combinations of peptides were screened at three different pHs and three analyte concentrations to generate 441 different conditions.…”

Section: Combinatorial Peptide Macro Array Assaymentioning

confidence: 99%

Modular peptides from the thermoplastic squid sucker ring teeth form amyloid-like cross-β supramolecular networks

et al. 2016

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. (2016). Modular peptides from the thermoplastic squid sucker ring teeth form amyloid-like cross-supramolecular networks. Acta Biomaterialia. https://doi.org/10.1016/j.actbio.2016.09.040Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Take down policy If you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access to the work immediately and investigate your claim. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe hard sucker ring teeth (SRT) from decapodiforme cephalopods, which are located inside the sucker cups lining the arms and tentacles of these squid species, have recently emerged as a unique model structure for biomimetic structural biopolymers. SRT are entirely composed of modular, block co-polymer-like proteins that self-assemble into a large supramolecular network. In order to unveil the molecular principles behind the SRT's self-assembly and robustness, we describe a combinatorial screening assay that maps the molecular-scale interactions between the most abundant modular peptide blocks of suckerin proteins. By selecting prominent interaction hotspots from this assay, we identified four peptides that exhibited the strongest homo-peptidic interactions, and conducted further in-depth biophysical characterizations complemented by molecular dynamic (MD) simulations to investigate the nature of these interactions. Circular Dichroism (CD) revealed conformations that transitioned from semi-extended poly-proline II (PII) towards β-sheet structure. The peptides s...

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“…The OBOC library LWH-01 was synthesized on TentaGel resin beads using a standard solid phase ''split/mix'' approach [26][27][28] (Supplementary Table S1; Supplementary Data are available at www.liebertpub.com/met/.). In brief, TentaGel beads (2.0 grams, at 0.26 mmol/gram) were swollen in N,N¢-dimethylformamide (DMF) for 3 hr.…”

Section: Synthesis Of the Oboc Librariesmentioning

confidence: 99%

Synthesis and Characterization of a Novel Inhibitor of C-Reactive Protein–Mediated Proinflammatory Effects

Kumaresan

Devaraj

Huang

et al. 2013

Metabolic Syndrome and Related Disorders

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Background: Numerous studies have shown that high C-reactive protein (CRP) levels predict cardiovascular disease and augur a poor prognosis in patients with acute coronary syndromes. Much in vitro and in vivo data support of a role for CRP in atherogenesis. There is an urgent need to develop inhibitors that specifically block the biological effects of CRP in vivo. The one-bead-one-compound (OBOC) combinatorial library method has been used to discover ligands against several biological targets. In this study, we use a novel fluorescence-based screening method to screen an OBOC combinatorial library for the discovery of peptides against human CRP. Methods: Human CRP was labeled with fluorescein isothiocyanate (FITC) and human serum albumin (HuSA) was labeled with phycoerythrin (PE) and used for screening. The OBOC library LWH-01 was synthesized on TentaGel resin beads using a standard solid-phase ''split/mix'' approach. Results: By subtraction screening, eight peptides that bind specifically to CRP and not to HuSA were identified. In human aortic endothelial cells (HAECs) incubated with CRP, inhibitors CRPi-2, CRPi-3, and CRPi-6 significantly inhibited CRP-induced superoxide, cytokine release, and nuclear factor-kB (NFkB) activity. Molecular docking studies demonstrate that CRPi-2 interacts with the two Ca 2 + ions in the single subunit of CRP. The binding of CRPi-2 is reminiscent of choline binding. Conclusions: Future studies will examine the utility of this inhibitor in animal models and clinical trials.

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The “One-Bead-One-Compound” Combinatorial Library Method

Cited by 751 publications

References 338 publications

High-throughput in vivo screening of targeted molecular imaging agents

High-throughput in vivo screening of targeted molecular imaging agents

Modular peptides from the thermoplastic squid sucker ring teeth form amyloid-like cross-β supramolecular networks

Synthesis and Characterization of a Novel Inhibitor of C-Reactive Protein–Mediated Proinflammatory Effects

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