Probing of primed and unprimed sites of calpains: Design, synthesis and evaluation of epoxysuccinyl-peptide derivatives as selective inhibitors

Calpains are intracellular cysteine proteases with important physiological functions. Up- or downregulation of their expression can be responsible for several diseases, therefore specific calpain inhibitors may be considered as promising candidates for drug discovery. In this paper we describe the synthesis and characterization of a new class of inhibitors derived from the analysis of amino acid preferences in primed and unprimed sites of calpains by incorporation of l- or d-epoxysuccinyl group (Eps). Amino acids for replacement were chosen by considering the substrate preference of calpain 1 and 2 enzymes. The compounds were characterized by RP-HPLC, amino acid analysis and ESI-MS. Selectivity of the compounds was studied by using calpain 1 and 2; and cathepsin B. We have identified five calpain specific inhibitors with different extent of selectivity. Two of these also exhibited isoform selectivity. Compound NH 2-Thr-Pro-Leu-(d-Eps)-Thr-Pro-Pro-Pro-Ser-NH2 proved to be a calpain 2 enzyme inhibitor with at least 11.8-fold selectivity, while compound NH2-Thr-Pro-Leu-(l-Eps)-Ser-Pro-Pro-Pro-Ser-NH2 possesses calpain 1 enzyme inhibition with at least 4-fold selectivity. The results of molecular modeling calculations suggest that the orientation of the bound inhibitor in the substrate binding cleft is markedly dependent on the stereochemistry of the epoxysuccinyl group. © 2014 Elsevier Masson SAS. All rights reserved

On the nature of different types of absorbing states

We present a comparison of three different types of Langevin equation exhibiting absorbing states: the Langevin equation defining the Reggeon field theory, one with multiplicative noise, and a third type in which the noise is complex. Each one is found to describe a different underlying physical mechanism; in particular, the nature of the different absorbing states depends on the type of noise considered. By studying the stationary single-site effective potential, we analyze the impossibility of finding a reaction-diffusion model in the multiplicative noise universality class. We also discuss some theoretical questions related to the nature of complex noise, as for example, whether it is necessary or not to consider a complex equation in order to describe processes as the annihilation reaction, $A +A \to 0$.Comment: 7 figures, Latex fil

Rare region effects at classical, quantum, and non-equilibrium phase transitions

Rare regions, i.e., rare large spatial disorder fluctuations, can dramatically change the properties of a phase transition in a quenched disordered system. In generic classical equilibrium systems, they lead to an essential singularity, the so-called Griffiths singularity, of the free energy in the vicinity of the phase transition. Stronger effects can be observed at zero-temperature quantum phase transitions, at nonequilibrium phase transitions, and in systems with correlated disorder. In some cases, rare regions can actually completely destroy the sharp phase transition by smearing. This topical review presents a unifying framework for rare region effects at weakly disordered classical, quantum, and nonequilibrium phase transitions based on the effective dimensionality of the rare regions. Explicit examples include disordered classical Ising and Heisenberg models, insulating and metallic random quantum magnets, and the disordered contact process.Comment: Topical review, 68 pages, 14 figures, final version as publishe

Interface depinning versus absorbing-state phase transitions

According to recent numerical results from lattice models, the critical exponents of systems with many absorbing states and an order parameter coupled to a non-diffusive conserved field coincide with those of the linear interface depinning model within computational accuracy. In this paper the connection between absorbing state phase transitions and interface pinning in quenched disordered media is investigated. For that, we present a mapping of the interface dynamics in a disordered medium into a Langevin equation for the active-site density and show that a Reggeon-field-theory like description, coupled to an additional non-diffusive conserved field, appears rather naturally. Reciprocally, we construct a mapping from a discrete model belonging in the absorbing state with-a-conserved-field class to a discrete interface equation, and show how a quenched disorder is originated. We discuss the character of the possible noise terms in both representations, and overview the critical exponent relations. Evidence is provided that, at least for dimensions larger that one, both universality classes are just two different representations of the same underlying physics.Comment: 8 page

Two-Particle-Self-Consistent Approach for the Hubbard Model

Even at weak to intermediate coupling, the Hubbard model poses a formidable challenge. In two dimensions in particular, standard methods such as the Random Phase Approximation are no longer valid since they predict a finite temperature antiferromagnetic phase transition prohibited by the Mermin-Wagner theorem. The Two-Particle-Self-Consistent (TPSC) approach satisfies that theorem as well as particle conservation, the Pauli principle, the local moment and local charge sum rules. The self-energy formula does not assume a Migdal theorem. There is consistency between one- and two-particle quantities. Internal accuracy checks allow one to test the limits of validity of TPSC. Here I present a pedagogical review of TPSC along with a short summary of existing results and two case studies: a) the opening of a pseudogap in two dimensions when the correlation length is larger than the thermal de Broglie wavelength, and b) the conditions for the appearance of d-wave superconductivity in the two-dimensional Hubbard model.Comment: Chapter in "Theoretical methods for Strongly Correlated Systems", Edited by A. Avella and F. Mancini, Springer Verlag, (2011) 55 pages. Misprint in Eq.(23) corrected (thanks D. Bergeron