Structure-based design of HSPA5 inhibitors: From peptide to small molecule inhibitors

We identified nine small-molecule hit compounds of Heat shock 70 kDa protein 5 (HSPA5) from cascade in silico screening based on the binding modes of the tetrapeptides derived from the peptide substrate or inhibitors of Escherichia coli HSP70. Two compounds exhibit promising inhibition activities from cancer cell viability and tumor inhibition assays. The binding modes of the hit compounds provide a platform for development of selective small molecule inhibitors of HSPA5. (C) 2013 Elsevier Ltd. All rights reserved.

Structural-Functional Studies of Burkholderia cenocepacia D-Glycero-beta-D-manno-heptose 7-Phosphate Kinase (HldA) and Characterization of Inhibitors with Antibiotic Adjuvant and Antivirulence Properties

As an essential constituent of the outer membrane of Gram-negative bacteria, lipopolysaccharide contributes significantly to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic pathway therefore serves as a promising therapeutic target for antivirulence drugs and antibiotic adjuvants. Here we report the structural-functional studies of D-glycero-beta-D-manno-heptose 7-phosphate kinase (HldA), an absolutely conserved enzyme in this pathway, from Burkholderia cenocepacia. HldA is structurally similar to members of the PfkB carbohydrate kinase family and appears to catalyze heptose phosphorylation via an in-line mechanism mediated mainly by a conserved aspartate, Asp270. Moreover, we report the structures of HldA in complex with two potent inhibitors in which both inhibitors adopt a folded conformation and occupy the nucleotide-binding sites. Together, these results provide important insight into the mechanism of HldA-catalyzed heptose phosphorylation and necessary information for further development of HldA inhibitors.

Possession Taken by Theft and the Original Acquisition of Personal Property Rights

This paper queries the soundness of the view that wrongful possession (eg a thief’s possession of goods he has stolen) should be protected by the standard actions for interference with goods. It uses close historical analysis of the development of the relevant concepts through the cases to argue that this is not a proposition that is compelled on the authorities, nor one demanded as a matter of principle. It then abstracts to consider the implications of this argument at a theoretical level, exposing great need for development in the common law’s basic principles of possessory protection. It argues innovatively that the objects of the law might be better served by the creation of a more limited form of possessory protection, achieved through the possessor’s acquisition of a personal right, and correlatively that the values that underpin and justify our basic rules of possessory protection entail a more nuanced response to matters of property acquisition.

The Revival of Private Property and Its Limits in Post-Mao China

This monograph examines the nature and significance of the re-emergence of private property in rapidly changing post-Mao China.

In examining this issue, the study explores a key dichotomy in Chinese law, that is, ‘public versus private’, and examines the manner in which the Chinese define ownership. The study stresses the importance of lack of clarity in the boundaries between the public and the private in property rights.

While there is a limited move towards the recognition of private property in real estate in contemporary China, this analysis also shows that ownership in the law, and ownership as understood and practised socially, often diverge significantly.

From the Qing dynasty reforms of the late nineteenth century onwards, ‘modernist’ law and entrenched social practice have often opposed each other. In contrast to the official, and indeed legal, support for unitary and exclusive property rights, the reality of the property regime has been a fragmentation of property rights. ‘Modern’ conceptions and theories of property rights emerged in the context of nation-building from the late Qing onwards, and unitary and exclusive property rights were considered as ‘badges’ of modernity.

These conceptions and theories served (and still serve) the purposes of control and governance but were, and still are, often resisted in social practice and popular thinking, leading to alienation and conflict. As a result, analysis of the nature and the social and political implications of re-emerging private property rights provides important insights for our understanding of the changing nature of modern China.

Landmark Cases in Property Law

This book explores the development of basic principles of property law in leading cases. Each paper considers a case on land, personal property or intangibles, discussing what that case contributes to the dominant themes of property jurisprudence - how are property rights acquired? What is the content of property rights? What are the limits or boundaries of property? How are property rights extinguished? Individually and collectively, the papers identify a number of important themes for the doctrinal development of property institutions and their broader justification. These themes include: the obscure and incremental development of seemingly foundational principles, the role of instrumentalism in property reasoning, the influence of the law of tort on the scope of property doctrines, and the impact of Roman legal reasoning on the common law of property. One or more of these themes (and others) is revealed through careful case analysis in each paper and they are collected and critically explored in the editors' introduction. This makes for a coherent and provocative collection.

Characterization of physio-chemical processes and hydration kinetics in concretes containing supplementary cementitious materials using electrical property measurements

The current study monitors both the short- and long-term hydration characteristics of concrete using discretized conductivity measurements from initial gauging, through setting and hardening, the latter comprising both the curing and post-curing periods. In particular, attention is directed to the near-surface concrete as it is this zone which protects the steel from the external environment and has a major influence on durability, performance and service-life. A wide range of concrete mixes is studied comprising both plain Portland cement concretes and concretes containing fly-ash and ground granulated blast furnace slag. The parameter normalised conductivity was used to identify four distinct stages in the hydration process and highlight the influence of supplementary cementitious materials (SCM) on hydration and hydration kinetics. A relationship has been presented to account for the temporal decrease in conductivity, post 10-days hydration. The testing procedure and methodology presented lend itself to in-situ monitoring of reinforced concrete structures. (c) 2013 Elsevier Ltd. All rights reserved.

Atomistic investigation on the structure-property relationship during thermal spray nanoparticle impact

During thermal spraying, hot particles impact on a colder substrate. This interaction of crystalline copper nanoparticles and copper substrate is modelled, using MD simulation. The quantitative results of the impacts at different velocities and temperatures are evaluated using a newly defined flattening aspect ratio. This ratio between the maximum diameter after the impact and the height of the splat increases with increasing Reynolds numbers until a critical value is reached. At higher Reynolds numbers the flattening aspect ratio decreases again, as the kinetic energy of the particle leads to increasing substrate temperature and, therefore, decreases the substrate resistance. Thus, the particle penetrates into the substrate and deforms less.

Complement inhibitors for age-related macular degeneration

Given the relatively high prevalence of age-related macular degeneration (AMD) and the increased incidence of AMD as populations age, the results of trials of novel treatments are awaited with much anticipation. The complement cascade describes a series of proteolytic reactions occurring throughout the body that generate proteins with a variety of roles including the initiation and promotion of immune reactions against foreign materials or micro-organisms. The complement cascade is normally tightly regulated, but much evidence implicates complement overactivity in AMD and so it is a logical therapeutic target in the treatment of AMD.

Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: Development of a [3.3.0]-based series and other piperidine bioisosteres

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]​-​based series, e.g. I, displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was obsd., within this novel series and a no. of other piperidine bioisosteric cores.

Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: Development of a potent and CNS penetrant [3.1.0]-based lead

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]​-​based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclin. model of schizophrenia (prepulse inhibition)​.

Synergistic effects of proteasome inhibitor carfilzomib in combination with tyrosine kinase inhibitors in imatinib-sensitive and -resistant chronic myeloid leukemia models

The tyrosine kinase inhibitor (TKI) imatinib has transformed the treatment and outlook of chronic myeloid leukemia (CML); however, the development of drug resistance and the persistence of TKI-resistant stem cells remain obstacles to eradicating the disease. Inhibition of proteasome activity with bortezomib has been shown to effectively induce apoptosis in TKI-resistant cells. In this study, we show that exposure to the next generation proteasome inhibitor carfilzomib is associated with a decrease in ERK signaling and increased expression of Abelson interactor proteins 1 and 2 (ABI-1/2). We also investigate the effect of carfilzomib in models of imatinib-sensitive and -resistant CML and demonstrate a potent reduction in proliferation and induction of apoptosis in a variety of models of imatinib-resistant CML, including primitive CML stem cells. Carfilzomib acts synergistically with the TKIs imatinib and nilotinib, even in imatinib-resistant cell lines. In addition, we found that the presence of immunoproteasome subunits is associated with an increased sensitivity to carfilzomib. The present findings provide a rational basis to examine the potential of carfilzomib in combination with TKIs as a potential therapy for CML, particularly in imatinib-resistant disease.