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"Shaul, Jacob"
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A polyomavirus peptide binds to the capsid VP1 pore and has potent antiviral activity against BK and JC polyomaviruses
In pursuit of therapeutics for human polyomaviruses, we identified a peptide derived from the BK polyomavirus (BKV) minor structural proteins VP2/3 that is a potent inhibitor of BKV infection with no observable cellular toxicity. The thirteen-residue peptide binds to major structural protein VP1 with single-digit nanomolar affinity. Alanine-scanning of the peptide identified three key residues, substitution of each of which results in ~1000 fold loss of binding affinity with a concomitant reduction in antiviral activity. Structural studies demonstrate specific binding of the peptide to the pore of pentameric VP1. Cell-based assays demonstrate nanomolar inhibition (EC50) of BKV infection and suggest that the peptide acts early in the viral entry pathway. Homologous peptide exhibits similar binding to JC polyomavirus VP1 and inhibits infection with similar potency to BKV in a model cell line. Lastly, these studies validate targeting the VP1 pore as a novel strategy for the development of anti-polyomavirus agents.
Journal Article
Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis
Diarrhoeal disease caused by
Cryptosporidium
is a major cause of morbidity and mortality in young and malnourished children from low- and middle-income countries, with no vaccine or effective treatment. Here we describe the discovery of EDI048, a
Cryptosporidium
PI(4)K inhibitor, designed to be active at the infection site in the gastrointestinal tract and undergo rapid metabolism in the liver. By using mutational analysis and crystal structure, we show that EDI048 binds to highly conserved amino acid residues in the ATP-binding site. EDI048 is orally efficacious in an immunocompromised mouse model despite negligible circulating concentrations, thus demonstrating that gastrointestinal exposure is necessary and sufficient for efficacy. In neonatal calves, a clinical model of cryptosporidiosis, EDI048 treatment resulted in rapid resolution of diarrhoea and significant reduction in faecal oocyst shedding. Safety and pharmacological studies demonstrated predictable metabolism and low systemic exposure of EDI048, providing a substantial safety margin required for a paediatric indication. EDI048 is a promising clinical candidate for the treatment of life-threatening paediatric cryptosporidiosis.
EDI048 is a gastrointestinal-targeted
Cryptosporidium
PI(4)K inhibitor that undergoes a predictable metabolism and limits systemic exposure without compromising its anti-parasitic activity.
Journal Article
A VP2/3-derived peptide exhibits potent antiviral activity against BK and JC polyomaviruses by targeting a novel VP1 binding site
In pursuit of effective therapeutics for human polyomaviruses, we identified a peptide derived from the BK polyomavirus (BKV) minor structural proteins VP2/3 that is a potent inhibitor of BKV infection with no observable cellular toxicity. The thirteen amino acid peptide binds to major structural protein VP1 in a new location within the pore with a low nanomolar KD. Alanine scanning of the peptide identified three key residues, substitution of each of which results in ~1000-fold loss of affinity with a concomitant reduction in antiviral activity. NMR spectroscopy and an X-ray structurally-guided model demonstrate specific binding of the peptide to the pore of the VP1 pentamer that constitutes the BKV capsid. Cell-based assays with the peptide demonstrate nanomolar inhibition of BKV infection and suggest that the peptide likely blocks the viral entry pathway between endocytosis and escape from the host cell ER. The peptide motif is highly conserved among the polyomavirus clade, and homologous peptides exhibit similar binding properties for JC polyomavirus and inhibit infection with similar potency to BKV in a model cell line. Substitutions within VP1 or VP2/3 residues involved in VP1-peptide interaction negatively impact viral infectivity, potentially indicating the peptide-binding site within the VP1 pore is relevant for VP1-VP2/3 interactions. The inhibitory potential of the peptide-binding site first reported here may present a novel target for development of new anti-polyomavirus therapies. In summary, we present the first anti-polyomavirus inhibitor that acts via a novel mechanism of action by specifically targeting the pore of VP1.
Paper
Two distinct mechanisms of small molecule inhibition of LpxA acyltransferase essential for lipopolysaccharide biosynthesis
The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multidrug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA and compound 2 is an uncompetitive inhibitor targeting the LpxA-product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1, and was optimized using structural information to achieve improved antibacterial activity against wild type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme-product complexes in drug discovery.
Paper
Resistance to innovation : its sources and manifestations
Every year, about 25,000 new products are introduced in the United States. Most of these products fail—at considerable expense to the companies that produce them. Such failures are typically thought to result from consumers' resistance to innovation, but marketers have tended to focus instead on consumers who show little resistance, despite these \"early adopters\" comprising only 20 percent of the consumer population.
Shaul Oreg and Jacob Goldenberg bring the insights of marketing and organizational behavior to bear on the attitudes and behaviors of the remaining 80 percent who resist innovation. The authors identify two competing definitions of resistance: In marketing, resistance denotes a reluctance to adopt a worthy new product, or one that offers a clear benefit and carries little or no risk. In the field of organizational behavior, employees are defined as resistant if they are unwilling to implement changes regardless of the reasons behind their reluctance. Seeking to clarify the act of rejecting a new product from the reasons—rational or not—consumers may have for doing so, Oreg and Goldenberg propose a more coherent definition of resistance less encumbered by subjective, context-specific factors and personality traits. The application of this tighter definition makes it possible to disentangle resistance from its sources and ultimately offers a richer understanding of consumers' underlying motivations. This important research is made clear through the use of many real-life examples.
eBook
Antibody optimization enabled by artificial intelligence predictions of binding affinity and naturalness
Traditional antibody optimization approaches involve screening a small subset of the available sequence space, often resulting in drug candidates with suboptimal binding affinity, developability or immunogenicity. Based on two distinct antibodies, we demonstrate that deep contextual language models trained on high-throughput affinity data can quantitatively predict binding of unseen antibody sequence variants. These variants span a KD range of three orders of magnitude over a large mutational space. Our models reveal strong epistatic effects, which highlight the need for intelligent screening approaches. In addition, we introduce the modeling of “naturalness”, a metric that scores antibody variants for similarity to natural immunoglobulins. We show that naturalness is associated with measures of drug developability and immunogenicity, and that it can be optimized alongside binding affinity using a genetic algorithm. This approach promises to accelerate and improve antibody engineering, and may increase the success rate in developing novel antibody and related drug candidates.
Paper
Two distinct mechanisms of small molecule inhibition of LpxA acyltransferase essential for lipopolysaccharide biosynthesis
ABSTRACT The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multidrug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA and compound 2 is an uncompetitive inhibitor targeting the LpxA-product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1, and was optimized using structural information to achieve improved antibacterial activity against wild type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme-product complexes in drug discovery.
Paper
The Systematics of Stable Hydrogen (δ2H) and Oxygen (δ18O) Isotopes and Tritium (3H) in the Hydrothermal System of the Yellowstone Plateau Volcanic Field, USA
To improve our understanding of hydrothermal activity on the Yellowstone Plateau volcanic field, we collected and analyzed a large data set of δ2H, δ18O, and the 3H concentrations of circum‐neutral and alkaline waters. We find that (a) hot springs are fed by recharge throughout the volcanic plateau, likely focused through fractured, permeable tuff units. Previous work had stressed the need for light δ2H water recharge restricted to the northern part of the plateau or recharge during past cold periods. However, new data from the Y‐7 drill hole suggests that recharge is not restricted to a certain area or a cold period. (b) δ18O values of thermal waters in the geyser basins are shifted from the global meteoric water line by temperature‐dependent water‐rock reactions with higher subsurface temperatures resulting in a greater shift. (c) Large temporal variations in the isotopic composition of meteoric water recharge and small temporal variability in the isotopic composition of hot spring discharge implies that the volume of groundwater in, and around the Yellowstone caldera is substantially larger than the volume of annual water recharge. (d) Hot springs discharged through different rhyolitic units correlate with identifiable differences in δ2H and δ18O compositions, 3H concentrations, and water chemistry that imply equilibration at different temperatures and travel along different flow paths. (e) Based on measured 3H concentrations, we calculate that hot spring waters in the central part of the geyser basins mostly contain <2% post‐1950 meteoric water, whereas waters discharged at the basin margins contain larger fractions of post‐1950s meteoric water.
Journal Article