Display omitted
•Medium-sized macrocycles can address novel disease-relevant targets.•Protein epitope mimetics (PEM) are mimics β-hairpin and α-helical protein epitopes.•PEM molecules can be ...efficiently synthesized using high-throughput parallel synthesis.•A summary of PEM molecules in clinical development is given.
Fully synthetic medium-sized macrocyclic peptides mimicking the key β-hairpin and α-helical protein epitopes relevant in many protein–protein interactions have emerged as a novel class of drugs with the potential to fill an important gap between small molecules and proteins. Conformationally stabilized macrocyclic scaffolds represent ideal templates for medicinal chemists to incorporate bioactive peptide and protein pharmacophores in order to generate novel drugs to treat diseases with high unmet medical need. This review describes recent approaches to design and generate large libraries of such macrocycles, for hit identification, and for their efficient optimization. Finally, this review describes some of the most advanced protein epitope mimetic (PEM) macrocycles in clinical development.
This review covers some of the recent progress in the field of peptide antibiotics with a focus on compounds with novel or established mode of action and with demonstrated efficacy in animal ...infection models. Novel drug discovery approaches, linear and macrocyclic peptide antibiotics, lipopeptides like the polymyxins as well as peptides addressing targets located in the plasma membrane or in the outer membrane of bacterial cells are discussed.
•Review article covering recent progress in the field of peptide antibiotics.•Peptide antibiotics with antimicrobial efficacy demonstrated in vivo.•Peptide antibiotics with novel and established modes of action and targets.•Addressed targets are at the outer or inner membrane, or in the cytoplasm.•Targets include LPS transport and outer membrane protein folding.
Impoundments in the midcontinent region of the United States provide the beneficial services of lentic waters. These impoundments were constructed long after intensified agriculture was established, ...and most are eutrophic. Total phosphorus (TP) increases in regional streams and reservoirs, concurrent with the proportion of cropland in the watershed, serve as a surrogate for nutrient loading from agriculture. The potential impact of external loading of TP to these reservoirs is moderated by sedimentation of particulate P and plunging interflows during summer stratification. Hydrology has a strong influence on TP; cross-system analyses show TP more than doubles across the range of flushing rates found in Missouri reservoirs when other factors are held constant. This link between hydrology and TP suggests reservoir placement on the landscape and design criteria strongly influence trophic state. Temporal variation is such that summer mean TP typically ranges 2- or 3-fold in individual reservoirs, suggesting benefits of best management practices to reduce external loading may be masked by inherent variation. Eutrophication of a midcontinent reservoir from poultry litter has been documented. Expansion of industrialized animal production throughout the region suggests legacy P, and resulting eutrophication, will likely increase over time without regulation.
Jones JR, Obrecht DV, Thorpe AP. 2022. Limnological characteristics of Lake of the Ozarks (Missouri, USA): long-term assessment following formation of a reservoir series. Lake Reserv Manage. ...38:288-303.
Impoundment of Truman Lake in 1980 on the Osage River, above Lake of the Ozarks (LOTO), created a reservoir series. This analysis details the changes and processes over the ensuing 35 yr (1980-2014) in this large impoundment dominated by a longitudinal gradient along the mainstem. Temporal variation was determined by hydrology; seasonal mean total phosphorus (TP) ranged between 12 and 58 µg/L at the near-dam location, and hydrologic flushing during summer explained 82% of this variation. After dam closure, mineral suspended solids, attributed to channel scouring of erodible materials in the tailwater reach, declined over time, with a 50% reduction near the dam. Concurrently, organic suspended solids increased by 1 to 4%/yr in mid-reach locations, which indicates greater autotrophic production. Compared with other Missouri reservoirs, algal chlorophyll (Chl) averaged 1.6 times the value predicted from TP. Ratios of Chl:TP have increased over past decades concurrent with an increase in organic suspended solids and expansion of the ultraplankton (<11 µm) fraction of total Chl. Warm and dry conditions are associated with an increase in Chl in the ultra fraction, suggesting climate influence. A comparison with data collected prior to the closure of Truman Dam (1976-1979) provides incontrovertible evidence that light transmission has improved, and both Chl and Chl:TP have increased in LOTO. Formation of a reservoir series resulted in immediate and long-term changes in this major impoundment.
Dissolved organic matter (DOM) and particulate organic matter (POM) can influence biogeochemical processes in aquatic systems. An understanding, however, of the source, composition, and processes ...driving inland reservoir organic matter (OM) cycling at a regional scale over the long term is currently unexplored. Here, we quantify decadal patterns (> 20 yr) of DOM quantity and composition and POM in 40 reservoirs in the midcontinent United States. We built 184 Random Forest models to identify how the relative influence of watershed characteristics and limnological parameters on OM dynamics may vary over time and in synchrony with hydroclimatic anomalies. The reservoir OM quantity and composition varied nonmonotonically through time and in contrast to lake browning observed in the northern hemisphere. Reservoir DOM composition switched from humic and aromatic during wet summers to aliphatic, potentially autochthonous DOM during particularly prolonged dry summers in the mid‐2000s. The shift in reservoir DOM quantity and composition could be attributed to the change in time‐varying control of watershed and limnological factors mediated by the hydroclimatic conditions. Watershed control (e.g., percent crops) was predominant during wet summers, while the effect of reservoir morphology (e.g., maximum depth) and water quality parameters (e.g., Secchi depth, chlorophyll a) were evident during dry summers. Thus, future predictions of drier conditions may promote “greening” with negative implications for reservoir water quality and treated drinking water. Considering the nonlinear nature of reservoir OM dynamics and its controls will help to better mitigate water quality issues in these constructed systems increasingly impacted by global changes.
Jones JR, Thorpe AP, Obrecht DV. 2020. Limnological characteristics of Missouri reservoirs: synthesis of a long-term assessment. Lake Reserv Manage. 36:412-422.
Missouri reservoirs reflect their ...edaphic location in the midcontinent ecotone between historic prairies and forests. Most are small (median surface area of 28 ha) but provide essential services in a region with few natural lakes. Long-term summer monitoring data (1978-2016) show that they span the full trophic state range, with oligotrophic reservoirs in deep, forested valleys and eutrophic-hypereutrophic impoundments in agricultural regions. In regression analysis, row crop (a surrogate for agricultural nutrient loss) along with depth and flushing rate accounted for some two-thirds of variation among reservoir nutrients. Hydrology is a strong influence; total phosphorus (TP) effectively doubles between flushing rates of 0.25/yr and 2/yr when holding land cover and depth constant. Temporal variation characterizes these impoundments; many show >3-fold range in mean summer trophic state metrics, which is influenced by the volume and timing of annual inflow. This variation may mask gradual nutrient-driven changes in trophic state; based on simulation, doubling chlorophyll (Chl) in a given lake over 20 yr could be undetectable with routine summer monitoring. Some two-thirds of cross-system variation in mean Chl was explained by TP, and inorganic solids further reduced variation (negative coefficient). On average, Chl:TP ratios increased from 0.28 to 0.48 during summer, coincident with a decline in inorganic solids. Inorganic particulates largely determine Secchi transparency and can result in light limitation of phytoplankton. Small reservoirs cover nearly double the area of major impoundments worldwide and are known for an intensity of ecological processes, making this information relevant beyond the region.
Using a biologically relevant peptide or protein structure as a starting point for lead identification represents one of the most powerful approaches in modern drug discovery. Here, we focus on the ...protein epitope mimetic (PEM) approach, where folded 3D structures of peptides and proteins are taken as starting points for the design of synthetic molecules that mimic key epitopes involved in protein–protein and protein–nucleic acid interactions. By transferring the epitope from a recombinant to a synthetic scaffold that can be produced by parallel combinatorial methods, it is possible to optimize target affinity and specificity as well as other drug-like ADMET properties. The PEM technology is a powerful tool for target validation, and for the development of novel PEM-based drugs.
In lakes and reservoirs, climate change increases surface water temperatures, promotes thermal stability, and decreases hypolimnetic oxygen. Increased anthropogenic land-use and precipitation enhance ...nutrient and sediment supply. Together, these effects alter the light and nutrient dynamics constraining phytoplankton biomass and productivity. Given that lake and reservoir processes differ, and that globally, reservoir numbers are increasing to meet water demands, reservoir-centric studies remain underrepresented. In the agricultural midwest (USA), ubiquitous reservoirs experience eutrophy and hypolimnetic anoxia. Here, we explore influences of eutrophication and land-use on the proximate light and nutrient status of phytoplankton communities in 32 Missouri reservoirs. Light and nutrient status indicators include mixed layer irradiance, phosphorus (P) and nitrogen (N) stoichiometry/debts, photosynthetic efficiency, and photosynthetic-irradiance parameters. Contributing to the ongoing P versus N and P management debate, we evaluate if phytoplankton biomass and productivity are constrained by light, P, N, or a combination thereof, across gradients of trophic status and land-use during 2 contrasting wet and dry summers. Despite agricultural prevalence, P-deficiency is more prominent than either N- or light-deficiency. In 2018, ~46% of samples were P-deficient with ~36% indicating neither light nor nutrient deficiency. Gross primary productivity per unit chlorophyll-a (GPPB) demonstrated negative relationships with nutrients, biomass, and turbidity, and positive relationships with light availability. Subsequently, GPPB was highest in oligotrophic reservoirs where light utilization efficiency was also highest. Overall, phytoplankton biomass and productivity appear constrained by P and light, respectively. If midwestern reservoirs are precursors of future inland waters affected by climate change and eutrophication, our crystal ball indicates that both P and light will be important regulators of phytoplankton dynamics and subsequent water quality.
PDF
