Trispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections.

Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4 and CD8 T cells.

Early Successes in an Open Access, Provincially Funded Hepatitis C Treatment Program in Prince Edward Island.

Introduction: The availability of curative hepatitis C therapies has created an opportunity to improve treatment delivery and access. Local providers, government, industry, and community groups in Prince Edward Island developed an innovative province-wide care model. Our goal was to describe the first year of program implementation.

Early Successes in an Open Access, Provincially Funded Hepatitis C Treatment Program in Prince Edward Island.

Introduction: The availability of curative hepatitis C therapies has created an opportunity to improve delivery and access. Local providers, government, industry, and community groups in Prince Edward Island developed an innovative province-wide care model. Our goal was to describe the first year of program implementation.

Study of -Quinone Methide Precursors toward the Realkylation of Aged Acetylcholinesterase.

Acetylcholinesterase (AChE) is an essential enzyme that can be targeted by organophosphorus (OP) compounds, including nerve agents. Following exposure to OPs, AChE becomes phosphylated (inhibited) and undergoes a subsequent aging process where the OP-AChE adduct is dealkylated. The aged AChE is unable to hydrolyze acetylcholine, resulting in accumulation of the neurotransmitter in the central nervous system (CNS) and elsewhere.

Implications of Dynamic Occupancy, Binding Kinetics, and Channel Gating Kinetics for hERG Blocker Safety Assessment and Mitigation.

Blockade of the hERG potassium channel prolongs the ventricular action potential (AP) and QT interval, and triggers early after depolarizations (EADs) and torsade de pointes (TdP) arrhythmia. Opinions differ as to the causal relationship between hERG blockade and TdP, the relative weighting of other contributing factors, definitive metrics of preclinical proarrhythmicity, and the true safety margin in humans. Here, we have used in silico techniques to characterize the effects of channel gating and binding kinetics on hERG occupancy, and of blockade on the human ventricular AP.

Quantitative structure-activity relationship models of chemical transformations from matched pairs analyses.

The concepts of activity cliffs and matched molecular pairs (MMP) are recent paradigms for analysis of data sets to identify structural changes that may be used to modify the potency of lead molecules in drug discovery projects. Analysis of MMPs was recently demonstrated as a feasible technique for quantitative structure-activity relationship (QSAR) modeling of prospective compounds. Although within a small data set, the lack of matched pairs, and the lack of knowledge about specific chemical transformations limit prospective applications.

Fluorinated compounds in medicinal chemistry: recent applications, synthetic advances and matched-pair analyses.

In recent years, several new fluorinated functional groups have been employed in medicinal chemistry. This review will highlight some recent developments in this area. We draw attention to useful synthetic advances for the installation of fluorine-containing groups.

C2 hydroxyl group governs the difference in hydrolysis rates of methyl-α-D-glycero-D-guloseptanoside and methyl-β-D-glycero-D-guloseptanoside.

A computational investigation into the hydrolysis of two methyl septanosides, methyl-α-D-glycero-D-guloseptanoside and methyl-β-D-glycero-D-guloseptanoside was undertaken. These septanosides were chosen as model compounds for comparison to methyl pyranosides and allowed direct comparison of α versus β hydrolysis rates for a specific septanoside isomer. Results suggest that hydrolysis takes place without proceeding through a transition state, an observation that was suggested in previous computational studies on exocyclic bond cleavage of carbohydrates.

Jujitsu kick to the abdomen: a case of blunt abdominal trauma resulting in hematochezia and transient ischemic colitis.

Blunt abdominal trauma is a common presentation to the emergency department. Ischemic colitis is a rare complication of this and its possible sequelae are important for an emergency physician to recognize. A 21-year-old man presented to the emergency department with abdominal pain and hourly episodes of bright red blood per rectum shortly after being kicked in the stomach at his jujitsu class.

Butyrylcholinesterase and G116H, G116S, G117H, G117N, E197Q and G117H/E197Q mutants: a molecular dynamics study.

Butyrylcholinesterase (BuChE) is a stoichiometric bioscavenger against organophosphorus (OP) nerve agent poisoning, and efforts to make BuChE variants that are catalytically active against a wide spectrum of nerve agents have been ongoing for the last decade. In order to understand the structural consequences for BuChE, we carried out extensive molecular dynamics (MD) simulations on wild-type BuChE (PDB ID: 1P0I) and several known and new variants of this enzyme, but without the presence of any ligand in the active site. The MD simulations on WT-BuChE identified two labile orientations for the catalytic serine, and also showed the likelihood of a backdoor.

Computational Modeling of Human Paraoxonase 1: Preparation of Protein Models, Binding Studies, and Mechanistic Insights.

The enzyme human paraoxonase 1 (huPON1) has demonstrated significant potential for use as a bioscavenger for treatment of exposure to organophosphorus (OP) nerve agents. Herein we report the development of protein models for the human isoform derived from a crystal structure of a chimeric version of the protein (pdb ID: 1V04) and a homology model derived from the related enzyme diisopropylfluorophosphatase (pdb ID: 1XHR). From these structural models, binding modes for OP substrates are predicted, and these poses are found to orient substrates in proximity to residues known to modulate specificity of the enzyme.

Reaction profiles of the interaction between sarin and acetylcholinesterase and the S203C mutant: model nucleophiles and QM/MM potential energy surfaces.

The phosphonylation mechanism of AChE and the S203C mutation by sarin (GB) is evaluated using two reaction schemes: a small model nucleophile (ethoxide, CH(3)CH(2)O(-)) and quantum mechanical/molecular mechanical (QM/MM) simulations. Calculations utilizing small model nucleophiles indicate that the reaction barrier for addition to GB is the rate-limiting step for both ethoxide and ethyl thiolate (CH(3)CH(2)S(-)); moreover, the activation barrier for addition to the phosphorus center of GB by ethyl thiolate is significantly larger (13.2 kcal/mol) than for ethoxide (8.

Chemical synthesis of two series of nerve agent model compounds and their stereoselective interaction with human acetylcholinesterase and human butyrylcholinesterase.

Both G and V type nerve agents possess a center of chirality about phosphorus. The S(p) enantiomers are generally more potent inhibitors than their R(p) counterparts toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). To develop model compounds with defined centers of chirality that mimic the target nerve agent structures, we synthesized both the S(p) and the R(p) stereoisomers of two series of G type nerve agent model compounds in enantiomerically enriched form.

Hydrolysis of nerve agents by model nucleophiles: a computational study.

Density functional theory calculations were employed to study the reaction of five nerve agents with model nucleophiles, including EtX(-) and EtXH (X=O, S, Se) for serine, cysteine and selenocysteine, respectively. Calculations at the B3LYP/6-311++G(2d,p) level of theory predict an exothermic reaction between ethoxide and all of the nerve agents studied. As compared to EtO(-) as a nucleophile, these reactions become approximately 30 kcal/mol more endothermic for EtS(-), and by approximately 40 kcal/mol for EtSe(-).