Scanning Protein Surfaces with DNA-Encoded Libraries

Understanding the ligandability of a target protein, defined as the capability of a protein to bind drug-like compounds on any site, can give important stimuli to drug-development projects. For instance, inhibition of protein–protein interactions usually depends on the identification of protein surface binders. DNA-encoded chemical libraries (DELs) allow scanning of protein surfaces with large chemical space. Encoded library selection screens uncovered several protein–protein interaction inhibitors and compounds binding to the surface of G protein-coupled receptors (GPCRs) and kinases. The protein surface-binding chemotypes from DELs are predominantly chemically modified and cyclized peptides, and functional small-molecule peptidomimetics. Peptoid libraries and structural peptidomimetics have been less studied in the DEL field, hinting at hitherto less populated chemical space and suggesting alternative library designs. Roughly a third of bioactive molecules evolved from smaller, target-focused libraries. They showcase the potential of encoded libraries to identify more potent molecules from weak, for example, fragment-like, starting points.     

Quantifying community resilience based on fluctuations in visits to points-of-interest derived from digital trace data

This research establishes a methodological framework for quantifying community resilience based on fluctuations in a population''s activity during a natural disaster. Visits to points-of-interests (POIs) over time serve as a proxy for activities to capture the combined effects of perturbations in lifestyles, the built environment and the status of business. This study used digital trace data related to unique visits to POIs in the Houston metropolitan area during Hurricane Harvey in 2017. Resilience metrics in the form of systemic impact, duration of impact, and general resilience (GR) values were examined for the region along with their spatial distributions. The results show that certain categories, such as religious organizations and building material and supplies dealers had better resilience metrics—low systemic impact, short duration of impact, and high GR. Other categories such as medical facilities and entertainment had worse resilience metrics—high systemic impact, long duration of impact and low GR. Spatial analyses revealed that areas in the community with lower levels of resilience metrics also experienced extensive flooding. This insight demonstrates the validity of the approach proposed in this study for quantifying and analysing data for community resilience patterns using digital trace/location-intelligence data related to population activities. While this study focused on the Houston metropolitan area and only analysed one natural hazard, the same approach could be applied to other communities and disaster contexts. Such resilience metrics bring valuable insight into prioritizing resource allocation in the recovery process.     

Solution Structure and Dynamics of the Small Protein HVO_2922 from Haloferax volcanii

Past sequencing campaigns overlooked small proteins as they seemed to be irrelevant due to their small size. However, their occurrence is widespread, and there is growing evidence that these small proteins are in fact functionally very important in organisms found in all kingdoms of life. Within a global proteome analysis for small proteins of the archaeal model organism Haloferax volcanii, the HVO_2922 protein has been identified. It is differentially expressed in response to changes in iron and salt concentrations, thus suggesting that its expression is stress-regulated. The protein is conserved among Haloarchaea and contains an uncharacterized domain of unknown function (DUF1508, UPF0339 family protein). We elucidated the NMR solution structure, which shows that the isolated protein forms a symmetrical dimer. The dimerization is found to be concentration-dependent and essential for protein stability and most likely for its functionality, as mutagenesis at the dimer interface leads to a decrease in stability and protein aggregation.     

Optimal Pricing of Climate Risk

Computational Economics - The climate change model of Daniel et al. (Proc Natl Acad Sci USA 116(42):20886-20891, 2019. https://doi.org/10.1073/pnas.1817444116) is an important contribution to the...     

Discovery of 5′′‐Chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064): A Selective Orexin 2 Receptor Antagonist (2‐SORA) for the Treatment of Insomnia

The field of small‐molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof‐of‐concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX₁R and OX₂R), termed dual orexin receptor antagonists (DORAs), affording late‐stage development candidates including Merck’s suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX₁R or OX₂R alone has been hampered by the dearth of suitable subtype‐selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2‐SORA) series to afford a potent, orally bioavailable 2‐SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5‐disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P‐glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2‐SORA clinical candidate, 5′′‐chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064), in mouse, rat, dog, and rhesus sleep models.     

Fate of physical,chemical, and microbial contaminants in domestic wastewater following treatment by small constructed wetlands

In order to evaluate the efficacy of constructed wetlands for treatment of domestic wastewater for small communities located in rural areas, small-scale wetland mesocosms (400 L each) containing two treatment designs (a mixture of Typha, Scirpus, and Juncus species; control without vegetation) were planted into two depths (45 or 60 cm) with pea gravel. Each mesocosm received 19 L/day of primary-treated domestic sewage. Mesocosms were monitored (inflow and outflow samples) on a monthly basis over a 2-year period for pH, total suspended solids (TSS), 5-day biochemical oxygen demand (BOD(5)), total Kjeldahl nitrogen (TKN), dissolved oxygen (DO), and conductivity. Microbiological analyses included enumeration of fecal coliforms, enterococci, Salmonella, Shigella, Yersinia, and coliphage. Significant differences between influent and effluent water quality for the vegetated wetlands (p<0.05) were observed in TSS, BOD(5), and TKN. Increased DO and reduction in fecal coliform, enterococcus, Salmonella, Shigella, Yersinia, and coliphage populations also were observed in vegetated wetlands. Greatest microbial reductions were observed in the planted mesocosms compared to those lacking vegetation. Despite marked reduction of several contaminants, wetland-treated effluents did not consistently meet final discharge limits for receiving bodies of water. Removal efficiencies for bacteria and several chemical parameters were more apparent during the initial year compared to the second year of operation, suggesting concern for long-term efficiency and stability of such wetlands.     

Effects of an ozone-generating air purifier on indoor secondary particles in three residential dwellings

The use of indoor ozone generators as air purifiers has steadily increased over the past decade. Many ozone generators are marketed to consumers for their ability to eliminate odors and microbial agents and to improve health. In addition to the harmful effects of ozone, recent studies have shown that heterogeneous and homogeneous reactions between ozone and some unsaturated hydrocarbons can be an important source of indoor secondary pollutants, including free radicals, carbonyls, carboxylic acids, and fine particles. Experiments were conducted in one apartment and two detached single-family dwellings in Austin, TX, to assess the effects of an ozone generator on indoor secondary organic aerosol concentrations in actual residential settings. Ozone was generated using a commercial ozone generator marketed as an air purifier, and particle measurements were recorded before, during, and after the release of terpenes from a pine oil-based cleaning product. Particle number concentration, ozone concentration, and air exchange rate were measured during each experiment. Particle number and mass concentrations increased when both terpenes and ozone were present at elevated levels. Experimental results indicate that ozone generators in the presence of terpene sources facilitate the growth of indoor fine particles in residential indoor atmospheres. Human exposure to secondary organic particles can be reduced by minimizing the intentional release of ozone, particularly in the presence of terpene sources. PRACTICAL IMPLICATIONS: Past studies have shown that ozone-initiated indoor chemistry can lead to elevated concentrations of fine particulate matter, but have generally been completed in controlled laboratory environments and office buildings. We explored the effects of an explicit ozone generator marketed as an air purifier on the formation of secondary organic aerosol mass in actual residential indoor settings. Results indicate significant increases in number and mass concentrations for particles <0.7 microns in diameter, particularly when an ozone generator is used in the presence of a terpene source such as a pine oil-based cleaner. These results add evidence to the potentially harmful effects of ozone generation in residential environments.