Discovery of stylissatin A analogs exhibiting potent nitric oxide inhibition.
Bioorg Chem
; 124: 105841, 2022 07.
Article
en En
| MEDLINE
| ID: mdl-35523075
ABSTRACT
The cyclic peptide stylissatin A(STA) was obtained from the Papua New Guinean marine spongeStylissamassaas a potent nitric oxide (NO) inhibitor.Among its reported analogs,cyclo-{Glu6, Ala2}-STA1potentlyinhibited theinterleukin-2 and proliferation of T-cells indicating position 2 of sequence playing important part in biological activities of this compound.In current studies, second generation analogs of STAwere synthesizedaround its most active analog1by screening position 2 of analog1with different amino acid. All analogs2-6were identified by mass, and NMR techniques.The synthesized analogswere also evaluated against NO generation by lipopolysaccharide (LPS)-stimulated murine J774.2macrophages, ROS inhibition from whole blood phagocytes, and T-cell proliferation from Jurkat cells.All analogswere found to be inactive towards interleukin-2, T-cells proliferation, and ROS inhibition. The analog2showed a potent suppression of NO (IC50 = 46.0 ± 2.2 µM) that was superior to the activityreported for natural product STA.Further attempts to optimizeanalog2afforded new nitric oxide inhibitors2a-2fwhich were found less active than2.The analog2also downregulated the transcription of pro-inflammatory molecules, tumor necrosis factor-α, interlukin-1ß, caspase-1 and ASC which further highlights its anti-inflammatory and possible therapeutic potential. Analog2was non-toxic to BJ and Vero cell lines of normal mammalian origin.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Péptidos Cíclicos
/
Óxido Nítrico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Año:
2022
Tipo del documento:
Article