In Silico, In Vitro and In Vivo Toxicological Assessment of BPP-BrachyNH2, A Vasoactive Proline-Rich Oligopeptide from Brachycephalus ephippium

Abstract

BPP-BrachyNH 2 is a proline-rich oligopeptide (PRO) firstly identified in skin secretion of the frog Brachycephalus ephippium, which possess in vitro inhibitory activity of angiotensin-I converting enzyme (ACE) and endothelium-dependent vasorelaxant activity. Considering its potential application in the treatment of cardiovascular diseases, the present work assessed the toxicological profile of the BPP-BrachyNH 2 . The in silico toxicity prediction was performed from the best model obtained through the optimization of the FASTA query peptide. This prediction study revealed that BPP-BrachyNH 2 induced high predicted LD 50 values for both humans and rats, and then is well-tolerated in the recommended range. The MTT assay was applied for the in vitro cytotoxic evaluation in murine macrophages. In this assay, a decrease of cell viability was not observed. The in vivo acute toxicological study was performed after the intraperitoneal administration of BPP-BrachyNH 2 at doses of 5 and 50 mg/kg. After intraperitoneal administration, no death, alterations in behavioral parameters or weight gain curve was observed, as well as none in the serum biochemical parameters, and gross pathological and histopathological analyses. These observations demonstrates an acceptable safety profile for BPP-BrachyNH 2 , leading towards further studies focused on investigation of pharmacological and therapeutical applications for this peptide.

Epiisopilosine alkaloid has activity against Schistosoma mansoni in mice without acute toxicity

“…mansoni , we performed in vitro cytotoxicity tests. These assays are essential in the early stages of drug development as they provide an estimation of the starting dose and range of concentrations to be used in in vivo non-clinical stages [ 10 , 37 ]. Our results accord with findings reported for other imidazole compounds that did not demonstrate strong toxic activity in mammalian cells (acute toxicity and cytotoxicity) [ 38 ].…”

“…The predicted toxicity showed that EPIIS had a human maximum tolerated dose with value within preferred specifications. The pkCSM prediction of hERG inhibition considers the IC 50 values of about 360 compounds (for hERG I analysis) and molecular parameters of more 800 compounds (for hERG II analysis) [ 10 , 43 , 44 ]. In our study, the hERG II model, but not the hERG I model showed positive results.…”

“…In our study, the hERG II model, but not the hERG I model showed positive results. These data point to a possible cardiotoxic effect of EPIIS, but as different datasets were applied in the same model, the prediction results may show some variability, as was shown for the BPP-brachyNH2 peptide [ 10 ]. More investigations are needed in this respect in view of the known parasympathomimetic action of the drug on vertebrate heart and vascular smooth muscles.…”

“…These results highlighted the need to perform in vivo studies of EPIIS, primarily regarding its possible use in the treatment of schistosomiasis. Moreover, it is important to evaluate possible toxicity, as acute toxicity studies in animals are used to fulfill various requirements related to the control of risks to human health and the environment [ 9 , 10 ].…”

Novel angiotensin‐converting enzyme ( ACE ) inhibitory mechanism of peptides from Macadamia integrifolia antimicrobial protein 2 ( MiAMP2 )

“…Virtual screening methods can narrow down the number of compounds that actually require biological testing (Arcanjo et al, 2017).…”