Peptidyl diazomethylketones as cysteine protease inhibitors structurally based upon the inhibitory centers of cystatins

Six new putative cysteine protease inhibitors based upon sequences of the N-terminal binding fragments of rat cystatin A, bovine cystatin C and human cystatins D and S were synthesized, inhibitory activities of these compounds against papain and bovine cathepsin B were tested. Additionally, agar well diffusion test of their antibacterial activity against Streptococcus pyogenes was performed

NEPHRITOGENIC ACTIVITY OF STREPTOCOCCUS PYOGENES emm1 AND emm12 GENOTYPES ISOLATED FROM PATIENTS AND ASYMPTOMATIC CARRIERS

In this paper the nephritogenic activity of Streptococcus pyogenes genotype emm1 and emm12 clinical isolates from scarlet fever patients and healthy children was considered. As earlier established, strains of these types differ in Fc-binding profile, interacting with native IgG and immune complexes (IC), respectively. As expected, all the type emm1 strains bound native IgG; besides, ICs interacted only with strains from patients but not with those from carriers. In contrast, all type emm12 strains appeared to be negative for native IgG, whereas ICs were bound by strains from patients exclusively. None of the tested strains bound IgG3. By immunization of rabbits, binding of native IgG as well as ICs was associated with increasing of anti-IgG antibodies titer, formation of ICs, «crescent» deposition of IgG and C3-complement, local production of the proinflammatory cytokine TNFα, аnd also with accumulation of lymphocytes in kidney tissue. These signs indicated immune inflammation, leading to experimental membrane-proliferative glomerulonephritis (PSGN). It is known that PSGN development depends on IC-binding by tissue FcγR, on complement activation as well as on tissue infiltration by macrophages/monocytes. According to the data of morphometric evaluation the nephritogenic activity of the type emm12 strains exceeded those of type emm1. On testing of three IC-binding emm12 strains in six rabbits, typical PSGN developed in 5 of them and an abortive process in 1 animal. In case of five IgG-binding type emm1 strains, out of ten rabbits full-blown PSGN was observed only in 3 of them, but abortive changes in 5 and negative result in 2 animals. No pathologic changes were elicited by the «carrier» strains of either genotype; the inability of these to bind ICs, according to literature data, could be explained by mutation in the Mga-regulator gene thereby impeding M-proteins synthesis. We conclude that isolation of type emm12 IC-binding strains at acute streptococcal infection should be considered a high risk-factor for postinfectious sequelae development. The rabbit model of PSGN used in this research thus allowed to reveal some main stages and features of its pathogenesis