ALZHEIMERSDRUG · Discovery of drugs for the treatment and prevention of Alzheimer's disease

Periodic Report Summary 2 - ALZHEIMERSDRUG (Discovery of drugs for the treatment and prevention of Alzheimer's disease)

The overall objective of this project is to validate our model, design, synthesize, and test new drugs that interrupt the interaction of acetylcholine receptors with amyloid peptides for the treatment and prevention of Alzheimer’s disease. Specific aim 1. To validate our model experimentally, and determine the NMR structure of amyloid peptides, in complex with the major binding determinant of acetylcholine receptors. First soluble amyloid peptides corresponding to residues 17-34 of Abeta(1-42) and flanked by glutamates were purchased and purified by HPLC. The soluble amyloid peptide structure was determined using homonuclear NMR and found to adopt an alpha-helix conformation. The NMR structure of the soluble amyloid peptide was published in Bioscience report (http://www.ncbi.nlm.nih.gov/pubmed/25284368). Second, the amyloid peptide in complex with nicotinic acetylcholine receptor was determined based on fold homology, and found to adopt a beta-hairpin conformation. Our model was published in neurotoxicology (http://www.ncbi.nlm.nih.gov/pubmed/23022323), and was confirmed by much experimental data, such as (1) the picomolar affinity between amyloid peptides and the nicotinic acetylcholine receptor, (2) Residue Y190 of the acetylcholine receptor interacts with amyloid peptides, (3) Amyloid peptides competitively inhibit snake alpha-neurotoxin binding. Specific aim 2. To calculate and correlate motion of biomolecules with their biological mechanism. Calculate the secondary structure conversion of amyloid peptides. The secondary structure conversion of amyloid peptides was calculated using normal mode dynamics. The initial secondary structure of corresponded to the alpha-helix observed for the soluble amyloid peptide, and the final secondary structure corresponded to the beta-hairpin observed in amyloid plaques. This secondary structure conversion was described in both papers mentioned above. Specific aim 3. To develop computational tools for drug design, and specifically a high accuracy tool for structure based prediction of binding sites and affinity. Several computational tools for drug design were developed. First, a program for finding dihedral angle homology in the PDB was designed. The program named Phi-DAC is available at http://tarshish.md.biu.ac.il/~samsona and was published in Bioinformatics (http://www.ncbi.nlm.nih.gov/pubmed/25252780). Second, a program for predicting the drug binding site on proteins was developed. The program dubbed EXPOSITE is based on solvent accessibility changes accompanying normal mode dynamics. The program was described in detail in a manuscript and is currently submitted to PLOS Comp Biol. These programs, Phi-DAC and EXPOSITE are useful for computer aided prediction of drug binding sites in proteins. Specific aim 4. To computationally design drugs which interrupt the interaction of Alzheimer’s amyloid peptides with the acetylcholine receptor. Based on our model, and using the computer programs described above, we designed and synthesized several drugs which are predicted to interrupt the interaction of amyloid peptides with the nicotinic acetylcholine receptor. One such "drug" orresponded to the chemically modified snake toxin, cobrotoxin, in which all arginine residues were substituted with phenoxyglyoxal. Other drugs corresponded to chemically modified acetylcholine. The drugs were then sent to our collaborators who injected them into transgenic Alzheimer's mice. Our collaborators report that the drugs improve memory and cognition in behavioral tests and are superior to acetylcholine esterase inhibitors, rivastigmine, and physostigmine, commonly prescribed against Alzheimer´s disease. Our final results are expected to provide safer drug alternatives to rivastigmine and physostigmine which suffer from neurotoxic side effects.

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