Desenho de peptídeos com potencial para o tratamento da doença de Alzheimer: triagem de mutações, dinâmica molecular e bioquímica quântica focadas na afinidade de ligação do complexo Aducanumabe::aβ2-7

Abstract

Seven treatments are approved for Alzheimer's disease, but five of them only relieve symptoms and do not alter the course of the disease. Aducanumab (Adu) and Lecanemab (Lec) are novel disease-modifying anti-amyloid-beta (Aβ) human monoclonal antibodies that specifically target the pathophysiology of Alzheimer's disease (AD) and were recently approved for its treatment. However, their administration is associated with serious side effects and their use is limited to patients in the early stages of the disease. In the present study, mutation screening, molecular dynamics, and quantum biochemistry were used to outline the interfacial interactions of the Aducanumab::Aβ2-7 complex. Our analysis identified critical stabilizing contacts revealing up to 40% variation in the affinity of the Adu chains for Aβ2-7 depending on the conformation outlined. Remarkably, two complementarity determining regions (CDRs) of the Adu Heavy chain (HCDR3 and HCDR2) and one CDR of the Adu Light chain (LCDR3) accounted for approximately 77% of the affinity for Aβ2-7, confirming their critical role in epitope recognition. The S91Y mutation (on Adu’s light chain), originally reported to have the potential to increase the affinity of Adu for Aβ2-7, was shown to decrease its structural stability without significantly increasing the overall binding affinity. Mimetic peptides that have the potential to inhibit Aβ aggregation were designed using quantum mechanics and bioinformatic predictive tools. While quantum biochemistry suggested that the PEP-L3-L1/L2 and PEP-L3-C1/C2 peptides should have the greatest affinity for Aβ, prediction tools indicated that the PEP-H3-L and PEP-H3-C peptides had the greatest potential to cross the blood-brain barrier and the least susceptibility to proteases. The thioflavin T assays support the use of these peptides, particularly Pep-H3-L and Pep-H3-C, as potential drugs with great potential to act as inhibitors of Aβ peptide aggregation.