Laura L. Perissinotti

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In Europe, ivabradine has recently been approved to treat patients with angina who have intolerance to beta blockers and/or heart failure. Ivabradine is considered to act specifically on the sinoatrial node by inhibiting the If current (the funny current) to slow automaticity. However, in vitro studies show that ivabradine prolongs phase 3 repolarization in(More)
We report an investigation of the reaction between (S)-nitroso-l-cysteine ethyl ester and l-cysteine ethyl ester as a model of physiologically relevant transnitrosation processes. Our theoretical and experimental evidence clearly supports the existence of a nitroxyl disulfide intermediate in solution.
The DNA nucleotide thymidylate is synthesized by the enzyme thymidylate synthase, which catalyzes the reductive methylation of deoxyuridylate using the cofactor methylene-tetrahydrofolate (CH(2)H(4)folate). Most organisms, including humans, rely on the thyA- or TYMS-encoded classic thymidylate synthase, whereas, certain microorganisms, including all(More)
The nitroprusside ion [Fe(CN)(5)NO](2-) (NP) reacts with excess HS(-) in the pH range 8.5-12.5, in anaerobic medium ("Gmelin" reaction). The progress of the addition process of HS(-) into the bound NO(+) ligand was monitored by stopped-flow UV/Vis/EPR and FTIR spectroscopy, mass spectrometry, and chemical analysis. Theoretical calculations were employed for(More)
In this work we present for the first time an X-ray structure of a coordinated S-nitrosothiol obtained by reaction of the extremely reactive K[IrCl5NO] with benzylmercaptan in acetonitrile. This surprisingly stable compound, trans-K[IrCl4(CH3CN)N(O)SCH2Ph], was isolated in high yield (80%) and fully characterized by FTIR, 1H NMR, and ESI-MS. To our(More)
We have investigated the structure and the vibrational spectrum of peroxynitrite anion in aqueous solution by means of combined quantum-classical (QM/MM) molecular dynamics simulations. In our QM/MM scheme, the reactant was modeled using density functional theory with a Gaussian basis set and the solvent was described using the mean-field TIP4P and the(More)
One of the main culprits in modern drug discovery is apparent cardiotoxicity of many lead-candidates via inadvertent pharmacologic blockade of K+, Ca2+ and Na+ currents. Many drugs inadvertently block hERG1 leading to an acquired form of the Long QT syndrome and potentially lethal polymorphic ventricular tachycardia. An emerging strategy is to rely on(More)
The rapid delayed rectifier current IKr is one of the major K+ currents involved in repolarization of the human cardiac action potential. Various inherited or drug-induced forms of the long QT syndrome (LQTS) in humans are linked to functional and structural modifications in the IKr conducting channels. IKr is carried by the potassium channel Kv11.1 encoded(More)
Congenital and acquired (drug-induced) forms of the human long-QT syndrome are associated with alterations in Kv11.1 (hERG) channel-controlled repolarizing IKr currents of cardiac action potentials. A mandatory drug screen implemented by many countries led to a discovery of a large group of small molecules that can activate hERG currents and thus may act as(More)
Activators of hERG1 such as NS1643 are being developed for congenital/acquired long QT syndrome. Previous studies identify the neighborhood of L529 around the voltage-sensor as a putative interacting site for NS1643. With NS1643, the V1/2 of activation of L529I (-34 ± 4 mV) is similar to wild-type (WT) (-37 ± 3 mV; P > 0.05). WT and L529I showed no(More)