Arlene G. Corrêa
Arlene G. Corrêa (Department of Chemistry, Federal University of São Carlos, agcorrea@ufscar.br)
Synthesis of Natural Product and Analogs as Inhibitors of Cysteine Proteases
Cathepsins, also known as lysosomal cysteine peptidases, are members of the papain-like peptidase family, involved in different physiological processes. In addition, cathepsins are implicated in many pathological conditions. In this presentation, we will describe the synthesis and evaluation of a series of N-aryl anthranilic acids, acridones, and 4-quinolinones as inhibitors of cathepsins V and L. The kinetics revealed that compounds of the classes of acridones are reversible competitive inhibitors of the target enzyme with affinities in the low micromolar range. They represent promising lead candidates for the discovery of novel competitive cathepsin inhibitors with enhanced selectivity and potency. On the other hand, 4-quinolinones were noncompetitive inhibitors and N-arylanthranilic acids were uncompetitive inhibitors. More recently, new peptidomimetic epoxides were also identified as cathepsins K and L inhibitors.
The enzyme cruzain is the major cysteine protease from Trypanosomacruzi, the etiologic agent of American trypanosomiasis or Chagas’ disease, and has been selected as an attractive target for the development of novel trypanocidal drugs.We will describe the synthesis and inhibitory effects of a series of chalcone derivatives against cruzain, as well as our efforts in the immobilization of this enzyme. The use of immobilized capillary enzyme reactors (ICERs) for on-line ligand screening has been adopted as a new technique of HTS.
