title: The impact of binding of macrocyclic metal complexes on amyloid fibrillization of insulin and lysozyme.
abstract: Amyloid fibrils are insoluble protein aggregates whose accumulation in cells and tissues is connected with a range of pathological diseases. We studied the impact of 2 metal complexes (axially coordinated Hf phthalocyanine and iron (II) clathrochelate) on aggregation of insulin and lysozyme. For both proteins, the host-guest interaction with these compounds changes the kinetics of fibrillization and affects the morphology of final aggregates. The Hf phthalocyanine is a very efficient inhibitor of insulin fibrillization; in its presence, only very low amounts of fibrils with the diameters of 0.8 to 5 nm and spherical aggregates were found. Effective concentration of fibrillization inhibition (IC50) was estimated to be 0.11 ± 0.04 μM. The clathrochelate induced the formation of thin fibrils with the diameters of 0.8 to 2.5 nm; IC50was estimated as 20 ± 9 μM. The lysozyme fibrillization remained quite intensive in the presence of the studied compounds; they induced the formation of long filaments (the length up to 2.5 μm, the diameters of 1.5-3.5 nm). These fibrils noticeably differed from those of free lysozyme short linear species (the diameters of 3-5 nm, the length up to 0.6 μm). Thinning and elongation of fibrils suggest that the metal complexes bind mainly to the grooves of protofilaments; this hinders the stacking of early aggregates or protofilaments together but does not hinder their growth. The image of the fibril separated into 2 protofilaments allows suggesting that the fibril formation occurs via the growth of the parallel protofilaments with their subsequent twisting in the fibril. The changes of the lysozyme intrinsic fluorescence indicate that both metal complexes interact with the protein during the stage of the fibrillar seeds formation.
authors.affiliation: Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Vladyslava
authors.identifier: 0000-0001-8305-9398
authors.initials: V
authors.lastname: Kovalska
authors.affiliation: Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Chernii
authors.affiliation: Institute of Physics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Cherepanov
authors.affiliation: Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Mykhaylo
authors.initials: M
authors.lastname: Losytskyy
authors.affiliation: V.I. Vernadsky Institute of General and Inorganic Chemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Victor
authors.initials: V
authors.lastname: Chernii
authors.affiliation: V.I. Vernadsky Institute of General and Inorganic Chemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Oleg
authors.initials: O
authors.lastname: Varzatskii
authors.affiliation: Institute of Physics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Anton
authors.initials: A
authors.lastname: Naumovets
authors.affiliation: Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Yarmoluk
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000648:ultrastructure; D000818:Animals; D002645:Chickens; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry*; D006195:Hafnium / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000737:chemistry; D007328:Insulin / Q000737:chemistry*; D007501:Iron / Q000737:chemistry; D054833:Isoindoles; D007700:Kinetics; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D009113:Muramidase / Q000737:chemistry*; D066329:Protein Aggregates; D011485:Protein Binding; D012996:Solutions
chemical_list: D000682:Amyloid; D056831:Coordination Complexes; D007211:Indoles; D007328:Insulin; D054833:Isoindoles; D047028:Macrocyclic Compounds; D066329:Protein Aggregates; D012996:Solutions; D007501:Iron; C421864:hen egg lysozyme; D009113:Muramidase; C013647:phthalocyanine; D006195:Hafnium
keywords: Hf phthalocyanine; amyloid fibril; inhibitor; iron(II) clathrochelate; protein aggregation