Synthesis of rational modified natural peptides from Boana cordobae and evaluation as multitarget agents against Alzheimer’s disease

AVATANEO, LUISINA; SPINELLI, ROQUE; SANCHIS, IVAN; RIETMANN, ALVARO JOSE; ASCHEMACHER, NICOLAS; SIANO, ALVARO

Simposio; 6ta Reunión Internacional de Ciencias Farmacéuticas (RICiFa 2021); 2021

Risita

Alzheimer's disease (AD) is a complex neurological disorder associated with different pathways, including cholinesterase enzymes (AChE and BChE), oxidative stress, biometals dyshomeostasis, among others. Because of this, a simultaneous modulation is needed. Previously, we have reported the natural peptides BcI-1202 and BcI-1190, isolated from Boana cordobae’s skin, with inhibitory activity against both cholinesterases. The aim of this work was the in-silico design and chemical synthesis of substitution analogs of BcI-1202 and BcI-1190. For this, specific residues were changed for a tryptophan residue to achieve the formation of π-π stacking interactions with catalytic residues of cholinesterases. The results showed that the substitution analogs increase the inhibitory activities against both cholinesterases, being the analogs with two tryptophan insertions the most active. In this regard, for BChE, BcI-1202 (A3/A6  W3/W6) showed a 30-fold decrement in IC50 values (200μM to 6,50μM), while for BcI-1190 (S1/A4  W1/W4) the decrease for IC50 was 66-fold (400μM to 6,30μM). Concerning AChE, both modifications conferred potent inhibitory activity. On the other hand, the substitutions have given antioxidant and chelating capabilities. The tryptophan modifications allowed to obtain multitarget peptides against therapeutic pathways of AD. We propose this strategy as an innovative tool to increase or confer bioactivity