Genomic and metagenomic approaches to natural product chemistry

For many years, natural products have been a primary source of new molecules for the treatment of disease, and microorganisms have been a prolific source of these molecules. Recent studies have indicated, however, that many biosynthetic pathways are present in organisms for which no natural product can be associated, and only a small fraction of the microbial life present in the environment can be grown in culture. This indicates that if methods could be developed for the isolation of these pathways and production of their target molecules in heterologous hosts, great numbers of potentially valuable compounds might be discovered. In these investigations, large insert libraries of two microorganisms were constructed, one a bacterial artificial chromosome (BAC) library, the other a fosmid library, and two large insert fosmid libraries were constructed with DNA isolated from marine environmental samples. A mathematical formula was derived to estimate probabilities of cloning intact biosynthetic pathways with large insert genomic libraries and tested with a computer simulation. This indicated that even large pathways could be cloned intact in large insert libraries, provided there was an adequate size difference between the target pathway and the library inserts, and there was a concomitant increase in the size of the library with the targeting of these larger pathways. In addition, an investigation into a mixed marine culture sample lead to the identification of an unusual relationship between two bacteria for which extended co-culture leads to the production of pyocyanin. However, no useful biosynthetic pathways were located within the genomic libraries. It is concluded that significant improvements would be required to make this approach feasible for larger scale investigations. It is further concluded, on the basis of recent developments in the field, including a reduction in the cost of sequencing, improvements in techniques of whole-genome shotgun sequencing, and the development of recombination based cloning, that the employment of mass sequencing efforts and sequence-driven, recombinationbased cloning, might prove to be a more fruitful and efficient alternative to large-insert library construction for the isolation and expression of these pathways. A possible paradigm for the cloning of pathways on the basis of this technology is proposed

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

Discovery of sisunatovir (RV521), an inhibitor of respiratory syncytial virus fusion

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo

Increasing the conductivity of crystalline polymer electrolytes

Polymer electrolytes consist of salts dissolved in polymers ( for example, polyethylene oxide, PEO), and represent a unique class of solid coordination compounds. They have potential applications in a diverse range of all-solid-state devices, such as rechargeable lithium batteries, flexible electrochromic displays and smart windows(1-5). For 30 years, attention was focused on amorphous polymer electrolytes in the belief that crystalline polymer: salt complexes were insulators. This view has been overturned recently by demonstrating ionic conductivity in the crystalline complexes PEO6: LiXF6 (X=P, As, Sb); however, the conductivities were relatively low(6,7). Here we demonstrate an increase of 1.5 orders of magnitude in the conductivity of these materials by replacing a small proportion of the XF6- anions in the crystal structure with isovalent N(SO2CF3)(2)(-) ions. We suggest that the larger and more irregularly shaped anions disrupt the potential around the Li+ ions, thus enhancing the ionic conductivity in a manner somewhat analogous to the AgBr1-xIx ionic conductors(8). The demonstration that doping strategies can enhance the conductivity of crystalline polymer electrolytes represents a significant advance towards the technological exploitation of such materials.</p