DNA‐encoded chemical library technology was developed with the vision of its becoming a transformational platform for drug discovery. The hope was that a new paradigm for the discovery of ...low‐molecular‐weight drugs would be enabled by combining the vast molecular diversity achievable with combinatorial chemistry, the information‐encoding attributes of DNA, the power of molecular biology, and a streamlined selection‐based discovery process. Here, we describe the discovery and early clinical development of GSK2256294, an inhibitor of soluble epoxide hydrolase (sEH, EPHX2), by using encoded‐library technology (ELT). GSK2256294 is an orally bioavailable, potent and selective inhibitor of sEH that has a long half life and produced no serious adverse events in a first‐time‐in‐human clinical study. To our knowledge, GSK2256294 is the first molecule discovered from this technology to enter human clinical testing and represents a realization of the vision that DNA‐encoded chemical library technology can efficiently yield molecules with favorable properties that can be readily progressed into high‐quality drugs.
We describe the development of a DNA‐encoded small‐molecule technology platform, and its use in discovering the soluble epoxide hydrolase (sEH) inhibitor GSK2256294. This molecule progressed through preclinical development and entered a human clinical trial where it was found to be orally bioavailable and well tolerated, demonstrating potent and dose‐dependent inhibition of sEH.
Men
and
jobs
alike are characterized by a single
trait
, which may take on categorical values according to given population frequencies.
Men
arrive to the system following a Poisson process and wait ...till
jobs
are assigned to them. Jobs arrive to the system following another, independent, Poisson process. An arriving job must be assigned to a waiting man immediately, or be discarded, ensuing no gain. An assignment of a job to a man yields a higher gain if they match in trait, and a lower one if not. Each man waits a limited time for a job and leaves the system if unassigned by that time limit. It is stipulated that a man who arrives first has priority to either accept the pending job, or to pass it to the next man, who makes a similar decision. The last man in the line takes the job, or it is discarded. The individually optimal policy for each man is defined by some
critical time
for accepting a mismatched job. We solve for the critical times, depending on the mens’ place in the queue, and obtain expressions for the ensuing optimal value functions of this system, for expected gain. The model originates from the
utility-equity
dilemma in assigning live organs to patients on the national waiting list. The paper reports numerical comparison of the above policy with alternative ones, for several performance measures.
This paper revisits the deterministic joint vendor–buyer production‐inventory problem and assumes that the production rate can be controlled. To guard against unwarranted extreme solutions, such as ...too abrupt production or, on the other hand, everlasting production aligned with demand, we place lower and upper bounds on the production rate. In addition, we incorporate an independent upper bound on the overall cycle of producing and remaining idle. Through identifying several critical points of the production rate, we solve the resulting problem for the optimal triplet (P, Q, n), where P is the constant production rate, a key decision variable, Q is the entire lot size produced in a cycle, and n is the number of equal successive shipments of this lot to the buyer. Our own treatment is purely analytical, which adds value from a theoretical perspective. Worst values of the production rate, when the other decision values are optimal for P, are found. We prove that only two production rates, the lowest and the highest, can yield minimal joint costs, and we identify which of the two is optimal under given relative positions of the defined critical points. Numerical illustration indicates that the joint cost sharply increases for small values of the bound on the overall cycle length. This study highlights the importance of solving variants of the suggested model and of developing managerial alternatives that relax this constraint as much as possible.
DEL selections are binding assays conducted with mixtures of chemically diverse DNA-tagged ligands and a screening target. DEL selections use DNA sequence counts to measure target binding, where ...ideally higher affinity ligands will have higher counts than weaker affinity ligands. However, there is not always a clear relationship between DNA sequence count (assay signal) and binding affinity. This disconnect may be due to the fidelity of library chemistry, where reactions often do not go to completion, and also to repetitive rounds of binding and elution that are standard practice in most DEL selection experiments. We describe here a strategy that addresses both of these issues and provides a means to calculate ligand affinity from primary selection data. The reaction yields of selected compounds during DEL library synthesis can also be predicted with this method.
•Method for determining compound affinity from DNA encoded library selection data.•Improvement in the effectiveness of the DEL platform for ligand discovery.•Multipoint analysis of DEL selections.
Adipose tissue (AT) dysregulation is a key process in the pathophysiology of obesity and its cardiometabolic complications, but even if a growing body of evidence has been collected over recent ...decades, the underlying molecular basis of adiposopathy remains to be fully understood. In this context, mitochondria, the intracellular organelles that orchestrate energy production and undergo highly dynamic adaptive changes in response to changing environments, have emerged as crucial regulators of both white (WAT) and brown adipose tissue (BAT) metabolism and function. Given that the gut microbiota and its metabolites are able to regulate host metabolism, adipogenesis, WAT inflammation, and thermogenesis, we hypothesize that their frequently observed dysregulation in obesity could affect AT metabolism by exerting direct and indirect effects on AT mitochondria. By collecting and revising the current evidence on the connections between gut microbiota and AT mitochondria in obesity, we gained insights into the molecular biology of their hitherto largely unexplored crosstalk, tracing how gut microbiota may regulate AT mitochondrial function.
We analyze an integrated inventory supply chain and seek the optimal production lot, optimal production rate, and optimal (integer) number of shipments per production lot. An increasing need for ...higher operational efficiency, as well as growing competition among multiple products for a limited storage capacity, is driving retailers to require more frequent shipping. This imposes pressure on suppliers to share the shipping cost with retailers. The sharing ratio of the shipment cost has not previously been considered within the context of an integrated supply chain. Therefore, we contribute to the literature by investigating this entirely new parameter, assuming that the shipment cost is shared between a manufacturer and a retailer. We also consider a distributed supply chain in which each party optimizes its own cost. We analyze the problem of finding the optimal sharing ratio of the shipment cost for such a supply chain and show that there exists a specific choice of shipment cost-sharing ratio (set by the manufacturer) that results in total costs similar to those obtained in the integrated inventory model. We develop deterministic models that provides basic insights into the investigated problem. Through mathematical analysis of a nested-designs model, we provide intermediate results (which are of interest in their own right) as well as optimal analytical solutions. We show, through numerical examples, that in the scenario where each party optimizes its own cost, the manufacturer's shipment cost is a central control variable in the sense that it affects the costs of both parties.
The proteolysis targeting chimera (PROTAC) strategy results in the down-regulation of unwanted protein(s) for disease treatment. In the PROTAC process, a heterobifunctional degrader forms a ternary ...complex with a target protein of interest (POI) and an E3 ligase, which results in ubiquitination and proteasomal degradation of the POI. While ternary complex formation is a key attribute of PROTAC degraders, modification of the PROTAC molecule to optimize ternary complex formation and protein degradation can be a labor-intensive and tedious process. In this study, we take advantage of DNA-encoded library (DEL) technology to efficiently synthesize a vast number of possible PROTAC molecules and describe a parallel screening approach that utilizes DNA barcodes as reporters of ternary complex formation and cooperative binding. We use a designed PROTAC DEL against BRD4 and CRBN to describe a dual protein affinity selection method and the direct discovery of novel, potent BRD4 PROTACs that importantly demonstrate clear SAR. Such an approach evaluates all the potential PROTACs simultaneously, avoids the interference of PROTAC solubility and permeability, and uses POI and E3 ligase proteins in an efficient manner.
The permeability of plasma membrane aquaporins (PIPs) to small solutes other than water greatly diversifies their potential functions in plant development and metabolic processes. One such process is ...stress signalling in which hydrogen peroxide (H
O
) plays a major role. Based on transport assays carried out in yeast, there are differences in the degree to which PIPs of Arabidopsis thaliana, are permeable to H
O
and thus they may differentially facilitate transmembrane diffusion. Here, we test whether specific PIPs aid in the transmembrane diffusion of H
O
to such an extent that knocking-out PIPs affects plant phenotype. We examined changes in growth and morphology, including biomass accumulation, root system architecture and relative water content, as well as gas exchange, across two H
O
treatments in knockout mutants of A. thaliana.
We could infer that PIP-type aquaporins are permeable to H
O
in planta and that this permeability is physiologically relevant in a plant's response to oxidative stress. In particular, the lack of functional PIP2;3 confers resistance to exogenously applied H
O
indicating that it facilitates H
O
entry into root cells. Additionally, PIP1;1 and PIP2;6 were found to facilitate H
O
diffusion, while PIP2;2 is required for proper root growth under controlled conditions.
We conclude that PIPs are physiologically relevant conduits for H
O
diffusion in the A. thaliana roots and participate in the regulation of stress responses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although numerous studies have implicated TLR5, or its ligands, bacterial flagellins, in the pathogenesis of Crohn's disease (CD), genome-wide association studies (GWAS) have not reported ...associations with the TLR5 gene. We aimed to examine potential CD-associated TLR5 variants and assess whether they modified inflammatory responses to bacterial flagellins.
A two-stage study was carried out. In stage 1, we genotyped tagging single-nucleotide polymorphisms (tag-SNPs) in the TLR5 gene in a sample of CD cases (<20 years of age, N = 566) and controls (N = 536). Single SNP and haplotype analysis was carried out. In Stage 2, we assessed the functional significance of potential CD-associated variant(s) vis-à-vis effects on the inflammatory response to bacterial flagellin using HEK293T cells. We observed marginal association between a non-synonymous coding SNP rs5744174 (p = 0.05) and CD. Associations between SNP rs851139 that is in high linkage disequilibrium (LD) with SNP rs5744174 were also suggested (p = 0.07). Haplotype analysis revealed that a 3 marker haplotype was significantly associated with CD (p = 0.01). Functional studies showed that the risk allele (616F) (corresponding to the C allele of SNP rs5744174) conferred significantly greater production of CCL20 in response to a range of flagellin doses than the comparator allele (616L).
Our findings suggest that a non-synonymous coding variation in the TLR5 gene may confer modest susceptibility for CD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF