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Vitaly V Komnatnyy, Thomas E Nielsen, Katrine Qvortrup
High-throughput screening is an important component of the drug discovery process. The screening of libraries containing hundreds of thousands of compounds requires assays amenable to miniaturisation and automization. Combinatorial chemistry holds a unique promise to deliver structurally diverse libraries for early drug discovery. Among the various library forms, the one-bead-one-compound (OBOC) library, where each bead carries many copies of a single compound, holds the greatest potential for the rapid identification of novel hits against emerging drug targets...
June 11, 2018: Chemical Communications: Chem Comm
Hader E Elashal, Ryan D Cohen, Heidi E Elashal, Monika Raj
A novel one-bead one-compound (OBOC) dual ring-opening/cleavage approach for cyclic peptide sequencing was developed. The method selectively modifies serine, cysteine, threonine, and/or glutamic acid to an oxazolidinone-derived moiety, thereby increasing the susceptibility of the modified peptide backbone toward hydrolysis. The resulting linear peptide was then sequenced in 1 min by tandem mass spectrometry on a quadrupole time-of-flight instrument incorporating two-dimensional liquid chromatography and ion mobility spectrometry separation...
April 20, 2018: Organic Letters
Keitou Shu, Thomas Kodadek
One-bead one-compound (OBOC) libraries constructed by solid-phase split-and-pool synthesis are a valuable source of protein ligands. Most OBOC libraries are composed of oligoamides, particularly peptides, peptoids, and peptoid-inspired molecules. Further diversification of the chemical space covered by OBOC libraries is desirable. Toward this end, we report here that the proline-catalyzed asymmetric aldol reaction, developed by List and Barbas for solution-phase synthesis, also works well for coupling immobilized aldehydes and soluble ketones...
May 14, 2018: ACS Combinatorial Science
Osayemwenre Erharuyi, Scott Simanski, Patrick J McEnaney, Thomas Kodadek
One bead one compound (OBOC) libraries can be screened against serum samples to identify ligands to antibodies in this mixture. In this protocol, hit beads are identified by staining with a fluorescent labeled secondary antibody. When screens are conducted against two different sets of serum, antibodies, and ligands to them, can be discovered that distinguish the two populations. The application of DNA-encoding technology to OBOC libraries has allowed the use of 10 µm beads for library preparation and screening, which pass through a standard flow cytometer, allowing the fluorescent hit beads to be separated from beads displaying non-ligands easily...
January 29, 2018: Bioorganic & Medicinal Chemistry Letters
Nam Tran-Hoang, Thomas Kodadek
One-bead-one-compound (OBOC) libraries constructed by solid-phase split-and-pool synthesis are a valuable source of protein ligands. Most OBOC libraries are comprised of oligoamides, particularly peptides, peptoids, and peptoid-inspired molecules. Further diversification of the chemical space covered by OBOC libraries is desirable. Toward this end, we report here the efficient proline-catalyzed asymmetric Mannich reaction between immobilized aldehydes and soluble ketones and anilines. The reaction conditions do not compromise the amplification of DNA by the PCR...
February 12, 2018: ACS Combinatorial Science
Yuchen Tang, Yann Thillier, Ruiwu Liu, Xiaocen Li, Kit S Lam, Tingjuan Gao
We report an analytical method to determine peptide loading of "one-bead one-compound" (OBOC) combinatorial peptide libraries at single-bead level. The quantification is based on a linear relationship between the amount of N-terminal amino groups on individual peptide beads and the intensity of Raman signal obtained from a specifically designed reporter labeled on amino groups. Confocal Raman spectroscopy was employed to characterize peptide loading of beads with defined peptide sequences and from OBOC combinatorial peptide libraries...
July 5, 2017: Analytical Chemistry
Randy P Carney, Yann Thillier, Zsofia Kiss, Amir Sahabi, Jean Carlos Heleno Campos, Alisha Knudson, Ruiwu Liu, David Olivos, Mary Saunders, Lin Tian, Kit S Lam
Membrane active peptides (MAPs) represent a class of short biomolecules that have shown great promise in facilitating intracellular delivery without disrupting cellular plasma membranes. Yet their clinical application has been stalled by numerous factors: off-target delivery, a requirement for high local concentration near cells of interest, degradation en route to the target site, and in the case of cell-penetrating peptides, eventual entrapment in endolysosomal compartments. The current method of deriving MAPs from naturally occurring proteins has restricted the discovery of new peptides that may overcome these limitations...
May 8, 2017: ACS Combinatorial Science
Dake Hao, Wenwu Xiao, Ruiwu Liu, Priyadarsini Kumar, Yuanpei Li, Ping Zhou, Fuzheng Guo, Diana L Farmer, Kit S Lam, Fengshan Wang, Aijun Wang
Endothelial progenitor cells (EPCs) and endothelial cells (ECs) play a vital role in endothelialization and vascularization for tissue regeneration. Various EPC/EC targeting biomolecules have been investigated to improve tissue regeneration with limited success often due to their limited functional specificity and structural stability. One-bead one-compound (OBOC) combinatorial technology is an ultrahigh throughput chemical library synthesis and screening method suitable for ligand discovery against a wide range of biological targets, such as integrins...
April 21, 2017: ACS Chemical Biology
Xiangqian Jia, Qiuju Han, Zihua Wang, Yixia Qian, Yunhong Jia, Weizhi Wang, Zhiyuan Hu
Aminopeptidase N (APN/CD13) is closely related to the growth of cancers and is suggested as a suitable target for anti-cancer therapy. Based on the "one-bead-one-compound" (OBOC) approach on a microarray device, we screened out a novel affinity peptide LN (YEVGHRC). It was determined that LN could specifically recognize and bind to APN. Moreover, LN-functionalized liposomes (LN-LS) could achieve efficient nano-encapsulated drug delivery under APN-overexpressing tumor conditions in vitro and in vivo...
February 28, 2017: Biomaterials Science
Sebastian Wieczorek, Dario Remmler, Tiziana Masini, Zdravko Kochovski, Anna K H Hirsch, Hans G Börner
Tailor-made drug solubilizers are studied based on peptide-poly(ethylene glycol) conjugates, which exhibit peptide segments constituting binding motifs for the small-molecule drugs of interest to render them water-soluble. Suitable 7mer peptides are selected via combinatorial means by screening large one-bead-one-compound (OBOC) peptide libraries. The capability of the screening method to read out structural detail of the drugs is investigated by comparing three related photosensitizers (Chlorin E6 (Ce6), Pheophorbide A (Pba) and meta-tetra(hydroxyphenyl)chlorin (m-THPC), which are applicable for photodynamic cancer therapy...
March 15, 2017: Bioconjugate Chemistry
Zhichu Xiang, Xiaoliang Yang, Junjie Xu, Wenjia Lai, Zihua Wang, Zhiyuan Hu, Jiesheng Tian, Lingling Geng, Qiaojun Fang
A novel peptide (P75) targeting EGFR and HER2 is successfully screened from a one-bead-one-compound (OBOC) library containing approximately 2 × 105 peptides built with the aid of computational simulation. In vitro and in vivo analyses show that P75 binds to human epithelial growth factor receptor (EGFR) with nanomolar affinity and to epithelial growth factor receptor-2 (HER2) with a lower affinity but comparable to other reported peptides. The peptide is used to modify the surface of magnetosome nanoparticles (NPs) for targeted magnetic resonance imaging (MRI)...
January 2017: Biomaterials
Lina Y Hu, Kimberly A Kelly, Julie L Sutcliffe
Molecular imaging allows for the visualization of changes at the cellular level in diseases such as cancer. A successful molecular imaging agent must rely on disease-selective targets and ligands that specifically interact with those targets. Unfortunately, the translation of novel target-specific ligands into the clinic has been frustratingly slow with limitations including the complex design and screening approaches for ligand identification, as well as their subsequent optimization into useful imaging agents...
April 2017: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Lingling Geng, Zihua Wang, Xiangqian Jia, Qiuju Han, Zhichu Xiang, Dan Li, Xiaoliang Yang, Di Zhang, Xiangli Bu, Weizhi Wang, Zhiyuan Hu, Qiaojun Fang
Herein, computational-aided one-bead-one-compound (OBOC) peptide library design combined with in situ single-bead sequencing microarray methods were successfully applied in screening peptides targeting at human epidermal growth factor receptor-2 (HER2), a biomarker of human breast cancer. As a result, 72 novel peptides clustered into three sequence motifs which are PYL***NP, YYL***NP and PPL***NP were acquired. Particularly one of the peptides, P51, has nanomolar affinity and high specificity for HER2 in ex vivo and in vivo tests...
2016: Theranostics
Jaspal Singh, Daniel Lopes, D Gomika Udugamasooriya
Conventional one-bead one-compound (OBOC) library synthesis is typically used to identify molecules with therapeutic value. The design and synthesis of OBOC libraries that contain molecules with imaging or even potentially therapeutic and diagnostic capacities (e.g. theranostic agents) has been overlooked. The development of a therapeutically active molecule with a built-in imaging component for a certain target is a daunting task, and structure-based rational design might not be the best approach. We hypothesize to develop a combinatorial library with potentially therapeutic and imaging components fused together in each molecule...
September 2016: Biopolymers
Ruiwu Liu, Xiaocen Li, Wenwu Xiao, Kit S Lam
Cancer is one of the major and leading causes of death worldwide. Two of the greatest challenges in fighting cancer are early detection and effective treatments with no or minimum side effects. Widespread use of targeted therapies and molecular imaging in clinics requires high affinity, tumor-specific agents as effective targeting vehicles to deliver therapeutics and imaging probes to the primary or metastatic tumor sites. Combinatorial libraries such as phage-display and one-bead one-compound (OBOC) peptide libraries are powerful approaches in discovering tumor-targeting peptides...
February 2017: Advanced Drug Delivery Reviews
Choi-Fong Cho, Kyungheon Lee, Maria-Carmela Speranza, Fernanda C Bononi, Mariano S Viapiano, Leonard G Luyt, Ralph Weissleder, E Antonio Chiocca, Hakho Lee, Sean E Lawler
Molecular targeting using ligands specific to disease markers has shown great promise for early detection and directed therapy. Bead-based combinatorial libraries have served as powerful tools for the discovery of novel targeting agents. Screening platforms employing magnetic capture have been used to achieve rapid and efficient identification of high-affinity ligands from one-bead-one-compound (OBOC) libraries. Traditional manual methodologies to isolate magnetized "hit" beads are tedious and lack accuracy, and existing instruments to expedite bead sorting tend to be costly and complex...
June 13, 2016: ACS Combinatorial Science
Chun-Yi Wu, Don-Hong Wang, Xiaobing Wang, Seth M Dixon, Liping Meng, Sara Ahadi, Daniel H Enter, Chao-Yu Chen, Jason Kato, Leonardo J Leon, Laura M Ramirez, Yoshiko Maeda, Carolina F Reis, Brianna Ribeiro, Brittany Weems, Hsing-Jien Kung, Kit S Lam
Identifying "druggable" targets and their corresponding therapeutic agents are two fundamental challenges in drug discovery research. The one-bead-one-compound (OBOC) combinatorial library method has been developed to discover peptides or small molecules that bind to a specific target protein or elicit a specific cellular response. The phage display cDNA expression proteome library method has been employed to identify target proteins that interact with specific compounds. Here, we combined these two high-throughput approaches, efficiently interrogated approximately 10(13) possible molecular interactions, and identified 91 small molecule compound beads that interacted strongly with the phage library...
June 13, 2016: ACS Combinatorial Science
Alexander K Price, Andrew B MacConnell, Brian M Paegel
With the potential for each droplet to act as a unique reaction vessel, droplet microfluidics is a powerful tool for high-throughput discovery. Any attempt at compound screening miniaturization must address the significant scaling inefficiencies associated with library handling and distribution. Eschewing microplate-based compound collections for one-bead-one-compound (OBOC) combinatorial libraries, we have developed hνSABR (Light-Induced and -Graduated High-Throughput Screening After Bead Release), a microfluidic architecture that integrates a suspension hopper for compound library bead introduction, droplet generation, microfabricated waveguides to deliver UV light to the droplet flow for photochemical compound dosing, incubation, and laser-induced fluorescence for assay readout...
March 1, 2016: Analytical Chemistry
Maria C Martínez-Ceron, Silvana L Giudicessi, Soledad L Saavedra, Juan M Gurevich-Messina, Rosa Erra-Balsells, Fernando Albericio, Osvaldo Cascone, Silvia A Camperi
Solid phase screenings of one bead one compound (OBOC) libraries have been widely used to find ligands with pharmacological and analytical uses, and to purify or detect proteins in complex mixtures. To improve library screening, in the last years various strategies have been developed to avoid the selection of false positive beads and to obtain selective ligands. Currently, there is great interest in cyclic peptides because of their resistance to enzymatic degradation and higher selectivity compared to their linear counterparts...
2016: Current Pharmaceutical Biotechnology
Diana Lac, Chun Feng, Gaurav Bhardwaj, Huong Le, Jimmy Tran, Li Xing, Gabriel Fung, Ruiwu Liu, Holland Cheng, Kit S Lam
Nonspecific ligation methods have been traditionally used to chemically modify immunoglobulins. Site-specific ligation of compounds (toxins or ligands) to antibodies has become increasingly important in the fields of therapeutic antibody-drug conjugates and bispecific antibodies. In this present study, we took advantage of the reported nucleotide-binding pocket (NBP) in the Fab arms of immunoglobulins by developing indole-based, 5-fluoro-2,4-dinitrobenzene-derivatized OBOC peptide libraries for the identification of affinity elements that can be used as site-specific derivatization agents against both mono- and polyclonal antibodies...
January 20, 2016: Bioconjugate Chemistry
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