Covalent drugs can offer significant advantages over non-covalent drugs in terms of pharmacodynamics (i.e., target-binding properties).
View Article and Find Full Text PDFPeptides that are composed of an alternating pattern of α- and γ-amino acids are potentially valuable as metabolism-resistant bioactive agents. For optimal function, some kind of conformational restriction is usually required to either stabilize the dominant 12-helix, or else to divert the peptide away from this conformation in a controlled way. Herein, we explore stereoselective fluorination as a method for controlling the conformations of α/γ-hybrid peptides.
View Article and Find Full Text PDFSide chain-fluorinated amino acids are useful tools in medicinal chemistry and protein science. In this review, we outline some general strategies for incorporating fluorine atom(s) into amino acid side chains and for elaborating such building blocks into more complex fluorinated peptides and proteins. We then describe the diverse benefits that fluorine can offer when located within amino acid side chains, including enabling F NMR and F PET imaging applications, enhancing pharmacokinetic properties, controlling molecular conformation, and optimizing target-binding.
View Article and Find Full Text PDFIntroduction: Screening echocardiography, guided by the current World Heart Federation (WHF) criteria, has important limitations that impede the establishment of large-scale rheumatic heart disease (RHD) control programmes in endemic regions. The criteria misclassify a significant number of normal cases as borderline RHD. Prior attempts to simplify them are limited by incorporation bias due to the lack of an externally validated, accurate diagnostic test for RHD.
View Article and Find Full Text PDFUnlabelled: There are only about 7,100 adolescent and adult cheetahs () remaining in the wild. With the majority occurring outside protected areas, their numbers are rapidly declining. Evidence-based conservation measures are essential for the survival of this species.
View Article and Find Full Text PDFAims: The World Heart Federation (WHF) criteria identify a large borderline rheumatic heart disease (RHD) category that has hampered the implementation of population-based screening. Inter-scallop separations (ISS) of the posterior mitral valve leaflet, a recently described normal variant of the mitral valve, appears to be an important cause of mild mitral regurgitation (MR) leading to misclassification of cases as WHF 'borderline RHD'. This study aims to report the findings of the Echo in Africa project, a large-scale RHD screening project in South Africa and determine what proportion of borderline cases would be re-classified as normal if there were a systematic identification of ISS-related MR.
View Article and Find Full Text PDFWe live in a world characterized by biodiversity loss and global environmental change. The extinction of large carnivores can have ramifying effects on ecosystems like an uncontrolled increase in wild herbivores, which in turn can have knock-on impacts on vegetation regeneration and communities. Cheetahs (Acinonyx jubatus) serve important ecosystem functions as apex predators; yet, they are quickly heading towards an uncertain future.
View Article and Find Full Text PDFThe bacterial quorum sensing (QS) system is a target for non-lethal antibacterial agents that do not encourage the development of resistance. QS inhibitors commonly contain a polar "head" moiety and a lipidic "tail" moiety. In this work, we synthesised novel QS inhibitor candidates in which the lipidic "tail" is decorated with stereospecifically positioned fluorine atoms.
View Article and Find Full Text PDFProlyl hydroxylase (PHD) enzymes play a critical role in the cellular responses to hypoxia through their regulation of the hypoxia inducible factor α (HIF-α) transcription factors. PHD inhibitors show promise for the treatment of diseases including anaemia, cardiovascular disease and stroke. In this work, a pharmacophore-based virtual high throughput screen was used to identify novel potential inhibitors of human PHD2.
View Article and Find Full Text PDFIntroduction: The World Heart Federation (WHF) screening criteria do not incorporate a strict, reproducible definition of anterior mitral valve leaflet (AMVL) restriction. Using a novel definition, we have identified two distinct AMVL restriction configurations. The first, called "distal tip" AMVL restriction is associated with additional morphological features of rheumatic heart disease (RHD), while the second, "gradual bowing" AMVL restriction is not.
View Article and Find Full Text PDFPiperine, a natural product derived from peppercorns, has a variety of biological activities that make it an attractive lead compound for medicinal chemistry. However, piperine has some problematic physicochemical properties including poor aqueous solubility and a susceptibility to UV-induced degradation. In this work, we designed an analog of piperine in which the central conjugated hydrocarbon chain is replaced with a vicinal difluoroalkane moiety.
View Article and Find Full Text PDFObjective: The World Heart Federation (WHF) criteria incorporate a Doppler-based system to differentiate between 'physiological' and 'pathological' mitral regurgitation (MR)-a sole criterion sufficient for the diagnosis of WHF 'borderline' rheumatic heart disease (RHD). We have identified that interscallop separations (ISS) of the posterior mitral valve (MV) leaflet, can give rise to pathological MR in an otherwise-normal MV. We aimed to establish and compare the prevalence of ISS-related MR among South African children at high and low risk for RHD.
View Article and Find Full Text PDFVariability in habitat selection can lead to differences in fitness; however limited research exists on how habitat selection of mid-ranking predators can influence population-level processes in multi-predator systems. For mid-ranking, or mesopredators, differences in habitat use might have strong demographic effects because mesopredators need to simultaneously avoid apex predators and acquire prey. We studied spatially-explicit survival of cheetahs (Acinonyx jubatus) in the Mun-Ya-Wana Conservancy, South Africa, to test hypotheses related to spatial influences of predation risk, prey availability, and vegetation complexity, on mesopredator survival.
View Article and Find Full Text PDFStereoselectively-fluorinated analogs of pipecolic acid have been investigated through a combined theoretical and experimental approach. Three of the four possible diastereoisomers of 4,5-difluoropipecolic acid were successfully synthesized via deoxyfluorination chemistry, navigating a complex reaction network that included neighboring group participation, rearrangement, and elimination pathways. A DFT-based conformational study, supported by NMR J-based analysis, revealed that the different diastereoisomers of 4,5-difluoropipecolic acid preferentially adopt different puckers of the six-membered ring.
View Article and Find Full Text PDFCyclic peptides are promising scaffolds for drug development, attributable in part to their increased conformational order compared to linear peptides. However, when optimizing the target-binding or pharmacokinetic properties of cyclic peptides, it is frequently necessary to "fine-tune" their conformations, e.g.
View Article and Find Full Text PDFBackground: Studies determining the reliability of the World Heart Federation (WHF) anterior mitral valve leaflet (AMVL) measurement are limited by the introduction of bias in their test-retest analyses. This study sought to determine the reliability of the current AMVL measurement while controlling for systematic bias.
Methods: Retrospective analysis of echocardiographic data from 16 patients with previous acute rheumatic fever was performed.
Inflammatory bowel disease (IBD) is a chronic and life-long disease characterized by gastrointestinal tract inflammation. It is caused by the interplay of the host's genetic predisposition and immune responses, and various environmental factors. Despite many treatment options, there is no cure for IBD.
View Article and Find Full Text PDFAnthropogenic mortality of wildlife is typically inferred from measures of the absolute decline in population numbers. However, increasing evidence suggests that indirect demographic effects including changes to the age, sex, and social structure of populations, as well as the behavior of survivors, can profoundly impact population health and viability. Specifically, anthropogenic mortality of wildlife (especially when unsustainable) and fragmentation of the spatial distribution of individuals (home-ranges) could disrupt natal dispersal mechanisms, with long-term consequences to genetic structure, by compromising outbreeding behavior and gene flow.
View Article and Find Full Text PDFBackground: Tackling behavioural questions often requires identifying points in space and time where animals make decisions and linking these to environmental variables. State-space modeling is useful for analysing movement trajectories, particularly with hidden Markov models (HMM). Yet importantly, the ontogeny of underlying (unobservable) behavioural states revealed by the HMMs has rarely been verified in the field.
View Article and Find Full Text PDFGlobally, human activities have led to the impoverishment of species assemblages and the disruption of ecosystem function. Determining whether this poses a threat to future ecosystem stability necessitates a thorough understanding of mechanisms underpinning community assembly and niche selection. Here, we tested for niche segregation within an African small carnivore community in Kibale National Park, Uganda.
View Article and Find Full Text PDFThe population densities of leopards vary widely across their global range, influenced by prey availability, intraguild competition and human persecution. In Asia, particularly the Middle East and the Caucasus, they generally occur at the lower extreme of densities recorded for the species. Reliable estimates of population density are important for understanding their ecology and planning their conservation.
View Article and Find Full Text PDFIndividual specialization, when individuals exploit only a subset of resources utilized by the population, is a widespread phenomenon. It provides the basis for evolutionary diversification and can impact population and community dynamics. Both phenotypic traits and environmental conditions are predicted to influence individual specialization; however, its adaptive consequences are poorly understood, particularly among large mammalian carnivores that play an important role in shaping ecosystems.
View Article and Find Full Text PDFResearch on drivers of demographic rates has mostly focused on top predators and their prey, and comparatively less research has considered the drivers of mesopredator demography. Of those limited studies, most focused on top-down effects of apex predators on mesopredator population dynamics, whereas studies investigating alternative mechanisms are less common. In this study, we tested hypotheses related to top-down, bottom-up and density-dependent regulation of demographic rates in an imperilled mesopredator, the cheetah (Acinonyx jubatus).
View Article and Find Full Text PDF