Development and Applications of Topologically Segregated Bilayer Beads in One-bead One-compound Combinatorial Libraries

Liu, Ruiwu; Wang, Xiaobing; Song, Aimin; Bao, Tian; Lam, Kit S.

doi:10.1002/qsar.200540010

Cited by 21 publications

(29 citation statements)

References 66 publications

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“…A small molecule OBOC combinatorial library was synthesized on bilayer TG beads 36,37 (loading 0.26 mmol/g) using a similar approach as previously reported. 38 The synthetic approach is shown in Figure 1.…”

Section: Synthesis Of An Encoded Small Molecule Oboc Combinatorial LImentioning

confidence: 99%

High throughput screening of a small molecule one-bead-one-compound combinatorial library to identify attenuators of p21 as chemotherapy sensitizers

Park¹,

Wang²,

Liu³

et al. 2008

Cancer Biology & Therapy

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Kidney cancer is notoriously difficult to treat when metastatic due to its resistance to conventional chemotherapy. p21 is a cyclin kinase inhibitor which, in many tumor cell lines, conveys an antiapoptotic function through its induction by the DNA damage responsive p53 pathway, such that attenuation of p21 sensitizes several disparate cancer cell lines to DNA-damaging chemotherapy. Since clinical applications with therapeutic antisense and siRNA approaches are problematic, we sought to discover other methods to inhibit p21 which are more readily translatable to the clinic. Utilizing an on-bead enzyme-linked colorimetric binding assay, we screened a diverse one-bead-one-compound combinatorial small molecule library and identified 12 candidate compounds which bind p21. Each of the 12 candidate compounds was synthesized and tested individually and three ligands were found which had the highest p21 binding affinity and yielded similar chemical structure. These three compounds caused dose-dependent cytotoxicity as well as apoptosis when exposed to two RCC cell lines. In addition, these compounds sensitized cells to apoptosis when incubated with doxorubicin such that a lower dose of doxorubicin was required in the presence of the compounds for equivalent cell killing. Interestingly, a representative of the three compounds decreased p21 levels by specific induction of ubiquitin-dependent proteosome degradation. Thus, by high throughput screening of thousands of candidate small molecules, we have identified compounds which attenuate p21, cause RCC cell apoptosis and sensitize RCC cells to DNA-damaging chemotherapy. These compounds are currently being evaluated in in vivo assays as potential novel therapeutic for RCC.

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Section: Synthesis Of An Encoded Small Molecule Oboc Combinatorial LImentioning

confidence: 99%

High throughput screening of a small molecule one-bead-one-compound combinatorial library to identify attenuators of p21 as chemotherapy sensitizers

Park¹,

Wang²,

Liu³

et al. 2008

Cancer Biology & Therapy

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“…The focused libraries were synthesized on TentaGel resin utilizing the standard “split-mix” synthetic method (16). Topologically segregated bilayer beads were generated using a biphasic solvent approach (32). The library compounds were displayed on the 4% of the outer layer, and the coding peptide tags were synthesized on the bead interior.…”

Section: Resultsmentioning

confidence: 99%

Optimization of RGD-Containing Cyclic Peptides against αvβ3 Integrin

Wang

Xiao

Zhang³

et al. 2016

Molecular Cancer Therapeutics

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We have previously reported the use of one-bead-one-compound (OBOC) combinatorial technology to develop a disulfide cyclic, Arg-Gly-Asp containing octapeptide LXW7 (cGRGDdvc), that targets αvβ3 integrin with high affinity and specificity (Mol Cancer Ther, 9:2714–23, 2010). αvβ3 integrin is known to be over-expressed in many cancers and in tumor vasculature, and it has been established as a cancer therapeutic target. To further optimize LXW7, we have performed systematic structure activity relationship (SAR) studies. Based on the results, two highly focused OBOC peptide libraries were designed, synthesized and screened against αvβ3 integrin transfected K562 cells. One of the best ligands, LXW64 was found to have 6.6-fold higher binding affinity than LXW7, and showed preferential binding to cells expressing αvβ3 integrin. In addition to binding strongly to U-87MG glioblastoma cells in vitro, LXW64 also targets U-87MG xenografts implanted in nude mice, indicating that it is an excellent vehicle for delivery of cytotoxic payload to tumors and tumor blood vessels that overexpress αvβ3 integrin.

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“…This demonstrates a practical and universal strategy for screening peptide probes for different biological systems [235]. Due to the OBOC limitations in terms of high-throughput, recent reports have explored various alternatives, especially from the field of microfluidics [236]. On this matter, Li et al presented an innovative microfluidic combinatorial synthesis platform called microfluidic print-to-synthesis (MPS) or microfluidic impact printing (MI) [237,238].…”

Section: Combinatorial Microarray Screeningmentioning

confidence: 99%

Design, Screening, and Testing of Non-Rational Peptide Libraries with Antimicrobial Activity: In Silico and Experimental Approaches

et al. 2020

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One of the challenges of modern biotechnology is to find new routes to mitigate the resistance to conventional antibiotics. Antimicrobial peptides (AMPs) are an alternative type of biomolecules, naturally present in a wide variety of organisms, with the capacity to overcome the current microorganism resistance threat. Here, we reviewed our recent efforts to develop a new library of non-rationally produced AMPs that relies on bacterial genome inherent diversity and compared it with rationally designed libraries. Our approach is based on a four-stage workflow process that incorporates the interplay of recent developments in four major emerging technologies: artificial intelligence, molecular dynamics, surface-display in microorganisms, and microfluidics. Implementing this framework is challenging because to obtain reliable results, the in silico algorithms to search for candidate AMPs need to overcome issues of the state-of-the-art approaches that limit the possibilities for multi-space data distribution analyses in extremely large databases. We expect to tackle this challenge by using a recently developed classification algorithm based on deep learning models that rely on convolutional layers and gated recurrent units. This will be complemented by carefully tailored molecular dynamics simulations to elucidate specific interactions with lipid bilayers. Candidate AMPs will be recombinantly-expressed on the surface of microorganisms for further screening via different droplet-based microfluidic-based strategies to identify AMPs with the desired lytic abilities. We believe that the proposed approach opens opportunities for searching and screening bioactive peptides for other applications.

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Development and Applications of Topologically Segregated Bilayer Beads in One-bead One-compound Combinatorial Libraries

Cited by 21 publications

References 66 publications

High throughput screening of a small molecule one-bead-one-compound combinatorial library to identify attenuators of p21 as chemotherapy sensitizers

High throughput screening of a small molecule one-bead-one-compound combinatorial library to identify attenuators of p21 as chemotherapy sensitizers

Optimization of RGD-Containing Cyclic Peptides against αvβ3 Integrin

Design, Screening, and Testing of Non-Rational Peptide Libraries with Antimicrobial Activity: In Silico and Experimental Approaches

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