Truncation of Huia versabilis Bowman-Birk inhibitor increases its selectivity, matriptase-1 inhibitory activity and proteolytic stability

Agata Gitlin-Domagalska , Dawid Dębowski , Katarzyna Gucwa , Dominika Starego , Natalia Ptaszyńska , Adam Sieradzan , Agnieszka Karczyńska , Sergey Samsonov , Martin Mangold , Michael Gütschow , Anna Łęgowska , Krzysztof Rolka

Abstract

A gradual truncation of the primary structure of frog skin-derived Huia versabilis Bowman-Birk peptidic inhibitor (HV-BBI) resulted in 18-times stronger inhibitor of matriptase-1 (peptide 6, Ki = 8 nm) in comparison to the full-length HV-BBI (Ki = 155 nm). Analogous increase in the inhibitory activity in correlation with the peptide length reduction was not observed in case of other serine proteases, bovine trypsin (Ki = 151 nm for peptide 6 and Ki = 120 nm for HV-BBI) and plasmin (Ki = 120 nm for peptide 6 and 82 nm for HV-BBI). Weaker binding affinity to these enzymes emphasized an inhibitory specificity of peptide 6. Molecular dynamic analysis revealed that the observed variations in the binding affinity of peptide 6 and HV-BBI with matriptase-1 are associated with the entropic differences of the unbound peptides. Moreover, several aspects explaining differences in the inhibition of matriptase-1 by peptide 6 (bearing the C-terminal amide group) and its two analogues, peptide 6∗ (having the C-terminal carboxyl group, Ki = 473 nm) and cyclic peptide 6∗∗ (Ki = 533 nm), both exhibiting more than 50-fold reduced inhibitory potency, were discovered. It was also shown that peptide 6 presented significantly higher resistance to proteolytic degradation in human serum than HV-BBI. Additional investigations revealed that, in contrast to some amphibian-derived inhibitors, HV-BBI and its truncated analogues do not possess bactericidal activity, thus they cannot be considered as bifunctional agents.
Author Agata Gitlin-Domagalska (FCh/DMB/LBCh)
Agata Gitlin-Domagalska,,
- Laboratory of Bioorganic Chemistry
, Dawid Dębowski (FCh/DMB/LBCh)
Dawid Dębowski,,
- Laboratory of Bioorganic Chemistry
, Katarzyna Gucwa (FCh/DMB)
Katarzyna Gucwa,,
- Department of Molecular Biochemistry
, Dominika Starego (FCh/DMB/LBCh)
Dominika Starego,,
- Laboratory of Bioorganic Chemistry
, Natalia Ptaszyńska (FCh/DMB/LBCh)
Natalia Ptaszyńska,,
- Laboratory of Bioorganic Chemistry
, Adam Sieradzan (FCh/DTCh/LMM)
Adam Sieradzan,,
- Laboratory of Molecular Modeling
, Agnieszka Karczyńska (FCh/DTCh/LMM)
Agnieszka Karczyńska,,
- Laboratory of Molecular Modeling
, Sergey Samsonov (FCh/DTCh/LMM)
Sergey Samsonov,,
- Laboratory of Molecular Modeling
, Martin Mangold
Martin Mangold,,
-
, Michael Gütschow
Michael Gütschow,,
-
et al.`
Journal seriesBiochimie, ISSN 0300-9084, e-ISSN 1638-6183, (N/A 100 pkt)
Issue year2020
Vol171-172
Pages178-186
Publication size in sheets0.50
Keywords in Polishmatryptaza-1, peptydowe inhibitory wydzielone z płazów, dokowanie molekularne
Keywords in EnglishMatriptase-1, Amphibian-derived peptidic inhibitors, Molecular docking
ASJC Classification2700 General Medicine; 1303 Biochemistry
Abstract in PolishW pracy opisano chemiczną syntezę oraz aktywność inhibitorową wobec matryptazy-1 skróconych analogów inhibitora inhibitora Bowmana-Birki wyodrębnionego ze skóry żaby Huia versabilis. Jeden z otrzymanych peptydów wykazywał 18-krotnie wyższą aktywność niż natywny inhibitor o pełnej długości. Analiza dynamiki molekularnej wykazała, że w różnice w powinowactwie peptydów do enzymu korelują z efektami entropowymi.
DOIDOI:10.1016/j.biochi.2020.03.006
URL https://doi.org/10.1016/j.biochi.2020.03.006
Languageen angielski
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Gitlin_Domagalska_Agata_Truncation_of_Huia_versabilis_2020.pdf 1,41 MB
Score (nominal)100
Score sourcejournalList
ScoreMinisterial score = 100.0, 28-04-2020, ArticleFromJournal
Publication indicators WoS Citations = 0.000; Scopus SNIP (Source Normalised Impact per Paper): 2018 = 0.892; WoS Impact Factor: 2018 = 3.362 (2) - 2018=3.230 (5)
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