Small Structural Differences in Proline-Rich Decapeptides Have Specific Effects on Oxidative Stress-Induced Neurotoxicity and L-Arginine Generation by Arginosuccinate Synthase

Author(s)

Alberto-Silva, Carlos ; da Silva, Brenda Rufino ; da Silva, Julio Cezar Araujo ; Silva, Felipe Assumpcao da Cunha e ; Kodama, Roberto Tadashi ; da Silva, Wilmar Dias ; Costa, Maricilia Silva ; Portaro, Fernanda Calheta Vieira

• Document type: Journal article
• Source: PHARMACEUTICALS; v. 17, n. 7, p. 16-pg., 2024-07-01.

Abstract

Introduction. The proline-rich decapeptide 10c (Bj-PRO-10c; ENWPHPQIPP) from the Bothrops jararaca snake modulates arginino succinate synthetase (AsS) activity to stimulate L-arginine metabolite production and neuroprotection in the SH-SY5Y cell line. The relationships between structure, interactions with AsS, and neuroprotection are little known. We evaluated the neuro-protective effects of Bj-PRO-10c and three other PROs (Bn-PRO-10a, <ENWPRPKIPP; Bn-PRO-10a-MK, <ENWPRPKIPPMK; and, Bn-PRO-10c, <ENWPRPKVPP) identified from Bitis nasicornis snake venom, with a high degree of similarity to Bj-PRO-10c, on oxidative stress-induced toxicity in neuronal PC12 cells and L-arginine metabolite generation via AsS activity regulation. Methods. Cell integrity, metabolic activity, reactive oxygen species (ROS) production, and arginase activity were examined after 4 h of PRO pre-treatment and 20 h of H2O2-induced damage. Results. OnlyBn-PRO-10a-MK and Bn-PRO-10c restored cell integrity and arginase function under oxidative stress settings, but they did not reduce ROS or cell metabolism. The MK dipeptide in Bn-PRO-10a-MK and valine (V8) in Bn-PRO-10c are important to these effects when compared to Bn-PRO-10a.Bj-PRO-10c is not neuroprotective in PC12 cells, perhaps because of their limited NMDA-type glutamate receptor activity. The PROs interaction analysis on AsS activation can be rated as fol-lows:Bj-PRO-10c > Bn-PRO-10c > Bn-PRO-10a-MK > Bn-PRO-10a. The structure of PROs and their correlations with enzyme activity revealed that histidine (H5) and glutamine (Q7) in Bj-PRO-10cpotentiated their affinity for AsS. Conclusions. Our investigation provides the first insights intothe structure and molecular interactions of PROs with AsS, which could possibly further theirneuropharmacological applications. (AU)

• FAPESP's process: 23/03608-1 - Bioprospection of neuroprotective peptides from snake venoms in vitro and in vivo experimental models for the study of neurodegenerative diseases
• Grantee: Carlos Alberto da Silva
• Support Opportunities: Regular Research Grants