Computerized Drug Screening of the S31N Mutant of the Influenza A Virus

Influenza is responsible for millions of hospitalizations and deaths every year. Treating the influenza virus has become increasingly difficult since mutant viruses have rendered previously viable drugs ineffective. New drug-screening procedures are now necessary in order to speed up the process of viable drug discovery. Molecular simulations have proven valuable for studying drug effectiveness in wild-type flu viruses, but little has been done on prevailing influenza mutants. Influenza mutants often feature a change in the M2 proton channel, a critical component in the viral replication and infection cycle. To counter this, drugs must be discovered that can block the influenza M2 channel of mutant viruses. The purpose of this research report is to discuss the methods and results of using molecular dynamics simulations to predict drug efficacy against the M2 proton channel of the Influenza A virus

Sodium Flux Ratio in Voltage-Clamped Squid Giant Axons

The sodium flux ratio across the axolemma of internally perfused, voltage-clamped giant axons of Loligo pealei has been measured at various membrane potentials. The flux ratio exponent obtained from these measurements was about unity and independent of membrane voltage over the 50 mV range from about -20 to +30 mV. These results, combined with previous measurements of ion permeation through sodium channels, show that the sodium channel behaves like a multi-ion pore with two ion binding sites that are rarely simultaneously occupied by sodium

Two-, Three-, and Four-Particle Spatial Correlations Among Tertiary Cosmic Ray Muons

Showers of muons which result from interactions of primary cosmic rays high in the atmosphere appear deep underground as bundles of nearly parallel muons. For threshold energies of 1 TeV and arrival zenith angles of 45 degrees, those events having a small mean number of muons are described by a power law distribution in shower size having an exponent of ≅ -3.7 and a radial density distribution that decreases with distance R from the shower axis a little less rapidly than exp(-R/5.4 m). Comparison of new data on four muon spatial correlations in terms of the same phenomenology with data on two and three muon spatial correlations from previous experiments suggests that the shower size distribution steepens and the shower radial density distribution broadens with increasing shower size (i.e., with increasing mean energy of the primary cosmic ray at a given threshold energy of the muons observed). These results might be explained by a basically geometrical effect due either to a total inelastic cross section which rises with energy or by an enhanced contribution from the interactions of secondaries. If the effect does not have a geometrical origin, then it may be necessary to reformulate the input to shower development calculations which have assumed that interaction products axe described by factored, uncorrelated single particle statistical distributions. The relationships between the inclusive distributions predicted by theory and those of the empirical phenomenology are explored in.some detail

Fluorescence anisotropy of diphenylhexatriene and its cationic Trimethylamino derivative in liquid dipalmitoylphosphatidylcholine liposomes: opposing responses to isoflurane

<p>Abstract</p> <p>Background</p> <p>The mechanism of action of volatile general anesthetics has not yet been resolved. In order to identify the effects of isoflurane on the membrane, we measured the steady-state anisotropy of two fluorescent probes that reside at different depths. Incorporation of anesthetic was confirmed by shifting of the main phase transition temperature.</p> <p>Results</p> <p>In liquid crystalline dipalmitoylphosphatidylcholine liposomes, isoflurane (7-25 mM in the bath) increases trimethylammonium-diphenylhexatriene fluorescence anisotropy by ~0.02 units and decreases diphenylhexatriene anisotropy by the same amount.</p> <p>Conclusions</p> <p>The anisotropy data suggest that isoflurane decreases non-axial dye mobility in the headgroup region, while increasing it in the tail region. We propose that these results reflect changes in the lateral pressure profile of the membrane.</p

Copper Complexes as Influenza Antivirals: Reduced Zebrafish Toxicity

Copper complexes have previously been developed to target His37 in influenza M2 and are effective blockers of both the wild type (WT) and the amantadine-resistant M2S31N. Here, we report that the complexes were much less toxic to zebrafish than CuCl2. In addition, we characterized albumin binding, mutagenicity, and virus resistance formation of these metal complexes, and employed steered molecular dynamics simulations to explore whether the complexes would fit in M2. We also examined their anti-viral efficacy in a multi-generation cell culture assay to extend the previous work with an initial-infection assay, discovering that this is complicated by cell culture medium components. The number of copper ions binding to bovine serum albumin (BSA) correlates well with the number of surface histidines and BSA binding affinity is low compared to M2. No mutagenicity of the complexes was observed when compared to sodium azide. After 10 passages of virus in MDCK culture, the EC50 was unchanged for each of the complexes, i.e. resistance did not develop. The simulations revealed that the compounds fit well in the M2 channel, much like amantadine

Hydroxychloroquine Prophylaxis for COVID-19

It is common in medicine that simple, inexpensive remedies are held hostage to medical prejudice, financial or political interest, and legal precedent. The purpose of this review is to take the point of view of the victims of COVID-19 and address whether scientific information, including randomized-control trials, can answer whether the hydroxychloroquine should be dispensed for those testing positive and their immediate recent contacts at the point of testing. Although the FDA in the United States is yet to be convinced, the demonstration of positive effects in clinical trials cannot be ignored and there is a large amount of information in the pipeline (published pre-prints and registered clinical trials) that could tip the scales towards making the drug readily available for early disease and contact-prophylactic usage to reduce peak symptoms, symptom duration, contagiousness, hospitalizations and mortality. </jats:p