Design, synthesis and properties of novel powerful antioxidants, glutathione analogues.
Glutathione (GSH) is the major low-molecular weight antioxidant in mammalian cells. Thus, its analogues carrying similar and/or additional positive properties might have clinical perspectives. Here, we report the design and synthesis of a library of tetrapeptidic GSH analogues called UPF peptides. Compared to cellular GSH our designed peptidic analogues showed remarkably higher hydroxyl radical scavenging ability (EC(50) of GSH: 1,231.0 +/- 311.8 microM; EC(50) of UPF peptides: from 0.03 to 35 microM) and improved antiradical efficiency towards a stable alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) radical. The best of UPF peptides was 370-fold effective hydroxyl radical scavengers than melatonin (EC(50): 11.4 +/- 1.0 microM). We also found that UPF peptides do not influence the viability and membrane integrity of K562 human erythroleukemia cells even at 200 microM concentration. Dimerization of GSH and UPF peptides was compared in water and in 0.9% saline solutions. The results, together with an earlier finding that UPF1 showed protective effects in global cerebral ischemia model in rats, suggest that UPF peptides might serve both as potent antioxidants as well as leads for design of powerful non-peptidic antioxidants that correct oxidative stress-driven events.
Ehrlich
Kersti
K
Department of Biochemistry, National and European Centre of Excellence of Molecular and Clinical Medicine, University of Tartu, Tartu, Estonia. kersti.ehrlich@ut.ee
Viirlaid
Säde
S
Mahlapuu
Riina
R
Saar
Külliki
K
Kullisaar
Tiiu
T
Zilmer
Mihkel
M
Langel
Ulo
U
Soomets
Ursel
U
D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D019281:Dimerization; D015195:Drug Design; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D017665:Hydroxyl Radical; D020014:K562 Cells; D010851:Picrates
D000975:Antioxidants; D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D006834:Hydrazines; D010851:Picrates; D017665:Hydroxyl Radical; C004931:1,1-diphenyl-2-picrylhydrazyl; D005978:Glutathione