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Wei Jin

Bio: Wei Jin is an academic researcher from Scripps Research Institute. The author has contributed to research in topics: Promoter & Therapeutic gene modulation. The author has an hindex of 5, co-authored 5 publications receiving 297 citations.

Papers
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Journal ArticleDOI
TL;DR: In an effort to identify small molecules that would disrupt the interaction between the light-chain metalloprotease of BoNT serotype A and its cognate substrate, a multifaceted screening effort was undertaken and validate the use of high-throughput screening protocols to define previously unrecognized chemical scaffolds for the development of therapeutic agents to treat BoNT exposure.
Abstract: Among the agents classified as "Category A" by the U.S. Centers for Disease Control and Prevention, botulinum neurotoxin (BoNT) is the most toxic protein known, with microgram quantities of the protein causing severe morbidity and mortality by oral or i.v. routes. Given that this toxin easily could be used in a potential bioterrorist attack, countermeasures urgently are needed to counteract the pathophysiology of BoNT. At a molecular level, BoNT exerts its paralytic effects through intracellular cleavage of vesicle docking proteins and subsequent organism-wide autonomic dysfunction. In an effort to identify small molecules that would disrupt the interaction between the light-chain metalloprotease of BoNT serotype A and its cognate substrate, a multifaceted screening effort was undertaken. Through the combination of in vitro screening against an optimized variant of the light chain involving kinetic analysis, cellular protection assays, and in vivo mouse toxicity assays, molecules that prevent BoNT/A-induced intracellular substrate cleavage and extend the time to death of animals challenged with lethal toxin doses were identified. Significantly, the two most efficacious compounds in vivo showed less effective activity in cellular assays intended to mimic BoNT exposure; indeed, one of these compounds was cytotoxic at concentrations three orders of magnitude below its effective dose in animals. These two lead compounds have surprisingly simple molecular structures and are readily amenable to optimization efforts for improvements in their biological activity. The findings validate the use of high-throughput screening protocols to define previously unrecognized chemical scaffolds for the development of therapeutic agents to treat BoNT exposure.

117 citations

Journal ArticleDOI
TL;DR: High throughput screening of synthetic combinatorial small molecule libraries is used to identify inhibitors of arenavirus infection using pseudotyped virion particles bearing the glycoproteins of highly pathogenic arenaviruses, resulting in the discovery of a series of novel small molecule inhibitors of viral entry.

87 citations

Journal ArticleDOI
TL;DR: Characterization of a representative O-(acylamino) prodrug in vivo indicates that they approach the potency and exceed the efficacy of thefree drug itself (CBI-indole2), indicating that not only is the free drug effectively released from the inactive prodrug but also that they offer additional advantages related to a controlled or targeted release in vivo.
Abstract: N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of “reducing” nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N–O bond cleavage) increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (<0.1–0.01% free drug release), pH 7.0 phosphate buffer, and exhibit a robust half-life in human plasma (t½ = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicate that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2) indicating that not only is the free drug effectively released from the inactive prodrug, but that they offer additional advantages related to a controlled or targeted release in vivo.

55 citations

Journal ArticleDOI
James S. Stover1, Jin Shi1, Wei Jin1, Peter K. Vogt1, Dale L. Boger1 
TL;DR: The screening of a >9000 compound library of synthetic DNA binding molecules for selective binding to the consensus sequence of the transcription factor LEF-1 followed by assessment of the candidate compounds in a series of assays that characterized functional activity assures that activity in the final functional assay may be directly related to the inhibition of gene transcription and DNA binding properties of the identified molecules.
Abstract: The screening of a >9000 compound library of synthetic DNA binding molecules for selective binding to the consensus sequence of the transcription factor LEF-1 followed by assessment of the candidate compounds in a series of assays that characterized functional activity (disruption of DNA-LEF-1 binding) at the intended target and site (inhibition of intracellular LEF-1-mediated gene transcription) resulting in a desired phenotypic cellular change (inhibit LEF-1-driven cell transformation) provided two lead compounds: lefmycin-1 and lefmycin-2. The sequence of screens defining the approach assures that activity in the final functional assay may be directly related to the inhibition of gene transcription and DNA binding properties of the identified molecules. Central to the implementation of this generalized approach to the discovery of DNA binding small molecule inhibitors of gene transcription was (1) the use of a technically nondemanding fluorescent intercalator displacement (FID) assay for initial assessment of the DNA binding affinity and selectivity of a library of compounds for any sequence of interest, and (2) the technology used to prepare a sufficiently large library of DNA binding compounds.

34 citations

Journal ArticleDOI
TL;DR: One compound was identified that inhibits wild-type protease, as well as a drug-resistant protease with six mutations that suggests an allosteric non-competitive mechanism of inhibition and may represent a starting point for an additional strategy for anti-retroviral therapy.
Abstract: Clinically approved inhibitors of the HIV-1 protease function via a competitive mechanism. A particular vulnerability of competitive inhibitors is their sensitivity to increases in substrate concentration, as may occur during virion assembly, budding and processing into a mature infectious viral particle. Advances in chemical synthesis have led to the development of new high-diversity chemical libraries using rapid in-solution syntheses. These libraries have been shown previously to be effective at disrupting protein-protein and protein-nucleic acid interfaces. We have screened 44000 compounds from such a library to identify inhibitors of the HIV-1 protease. One compound was identified that inhibits wild-type protease, as well as a drug-resistant protease with six mutations. Moreover, analysis of this compound suggests an allosteric non-competitive mechanism of inhibition and may represent a starting point for an additional strategy for anti-retroviral therapy.

19 citations


Cited by
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Journal ArticleDOI
TL;DR: The general principles in protease-based drug discovery are discussed, highlighting the lessons learned and the emerging strategies, such as targeting allosteric sites, which could help harness the therapeutic potential of new protease targets.
Abstract: Proteases have an important role in many signalling pathways, and represent potential drug targets for diseases ranging from cardiovascular disorders to cancer, as well as for combating many parasites and viruses Although inhibitors of well-established protease targets such as angiotensin-converting enzyme and HIV protease have shown substantial therapeutic success, developing drugs for new protease targets has proved challenging in recent years This in part could be due to issues such as the difficulty of achieving selectivity when targeting protease active sites This Perspective discusses the general principles in protease-based drug discovery, highlighting the lessons learned and the emerging strategies, such as targeting allosteric sites, which could help harness the therapeutic potential of new protease targets

510 citations

Journal ArticleDOI
TL;DR: This review summarizes current knowledge on the structure of individual modules and presents mechanistic insights into how this protein machine evolved to this level of sophistication, thereby achieving an exquisite toxicity.
Abstract: Botulinum neurotoxin (BoNT), the causative agent of botulism, is acknowledged to be the most poisonous protein known. BoNT proteases disable synaptic vesicle exocytosis by cleaving their cytosolic SNARE (soluble NSF attachment protein receptor) substrates. BoNT is a modular nanomachine: an N-terminal Zn(2+)-metalloprotease, which cleaves the SNAREs; a central helical protein-conducting channel, which chaperones the protease across endosomes; and a C-terminal receptor-binding module, consisting of two subdomains that determine target specificity by binding to a ganglioside and a protein receptor on the cell surface and triggering endocytosis. For BoNT, functional complexity emerges from its modular design and the tight interplay between its component modules--a partnership with consequences that surpass the simple sum of the individual component's action. BoNTs exploit this design at each step of the intoxication process, thereby achieving an exquisite toxicity. This review summarizes current knowledge on the structure of individual modules and presents mechanistic insights into how this protein machine evolved to this level of sophistication. Understanding the design principles underpinning the function of such a dynamic modular protein remains a challenging task.

376 citations

Journal ArticleDOI
TL;DR: The use of carbon dioxide as a C1 building block for chemical synthesis has recently attracted much interest because of its abundance, low cost, nontoxicity, and high potential as a renewable source.
Abstract: The use of carbon dioxide (CO2) as a C1 building block for chemical synthesis has recently attracted much interest because of its abundance, low cost, nontoxicity, and high potential as a renewable source. However, the high thermodynamic stability and low reactivity of CO2 means that its use in C C bond-forming reactions usually requires organometallic reagents or other preactivated substrates such as organic halides (Scheme 1, routes a and b). Although the reaction of C H bonds with CO2 would be the most attractive and atom-economic route for the synthesis of carboxylic acids (Scheme 1, route c), the direct carboxylation of a C H bond with CO2 has remained a challenge. [4]

305 citations

Journal ArticleDOI
TL;DR: The basic understanding of the antibody structure is described along with how that knowledge has leveraged the engineering of antibody and antibody-related therapeutics having the appropriate antigen affinity, effector function, and biophysical properties to improve efficacy and manufacturability.
Abstract: Antibodies and antibody-derived macromolecules have established themselves as the mainstay in protein-based therapeutic molecules (biologics). Our knowledge of the structure–function relationships of antibodies provides a platform for protein engineering that has been exploited to generate a wide range of biologics for a host of therapeutic indications. In this review, our basic understanding of the antibody structure is described along with how that knowledge has leveraged the engineering of antibody and antibody-related therapeutics having the appropriate antigen affinity, effector function, and biophysical properties. The platforms examined include the development of antibodies, antibody fragments, bispecific antibody, and antibody fusion products, whose efficacy and manufacturability can be improved via humanization, affinity modulation, and stability enhancement. We also review the design and selection of binding arms, and avidity modulation. Different strategies of preparing bispecific and multispecific molecules for an array of therapeutic applications are included.

219 citations

Journal ArticleDOI
TL;DR: This review summarizes ongoing research aimed at finding novel drugs as alternatives to traditional antibiotics, including beta-lactamase inhibitors, which are already in clinical use and novel variants under investigation as well as efflux pump inhibitors.

171 citations