Rational design, synthesis and evaluation of modified natural peptides from Boana pulchella (anura) as inhibitors of human cholinesterases

IVAN, SANCHIS; BRAZZOLOTTO, XAVIER; DIAS, JOSE; AIMARETTI, FLORENCIA; HUMPOLA, MA. VERONICA; SIANO, ALVARO

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Congreso; 6ta Reunión Internacional de Ciencias Farmacéuticas. Academia Nacional de Farmacia y Bioquimica; 2021

Academia Nacional de Farmacia y Bioquimica

Cholinesterase inhibitors are the mostexploited compounds in the fight against Alzheimer’s disease (AD) and thoseacting on both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) areof special interest to drug developers. Some peptides with this property havebeen previously reported. In this work, we designed and synthesizedsubstitution derivatives of a natural cholinesterase inhibitor 10-mer peptide(LL) in order to increase its inhibitory activity. The design was guided by acomputational study of the inhibitor-enzyme complex, including flexible dockingand molecular dynamics simulations. Specific residues of LL peptide werereplaced by aromatics to introduce aromatic-aromatic interactions, since LL wasknown to act near key aromatic residues of cholinesterases. Peptides weresynthesized through solid FMOC synthesis and tested against both recombinanthuman AChE and BChE. Substitution of a proline with tryptophan resulted in animpressive 100-fold increase of the IC50 of AChE  (97.89±7.13µM to 0.99±0.02µM) and a12-fold of BChE IC50. This compound thus becomes the most activepeptide against cholinesterases ever reported. Another interesting derivativewith two tryptophans presented an AChE of 1.70±0.05µM and BChE IC50of 9.40±0.48µM, an over 20-fold increase for this latter. We proposethese sequences as potential scaffold candidates for the development of newanti-AD drugs.