Modulation of prion polymerization and toxicity by rationally designed peptidomimetics.
Misfolding and aggregation of cellular prion protein is associated with a large array of neurological disorders commonly called the transmissible spongiform encephalopathies. Designing inhibitors against prions has remained a daunting task owing to limited information about mechanism(s) of their pathogenic self-assembly. Here, we explore the anti-prion properties of a combinatorial library of bispidine-based peptidomimetics (BPMs) that conjugate amino acids with hydrophobic and aromatic side chains. Keeping the bispidine unit unaltered, a series of structurally diverse BPMs were synthesized and tested for their prion-modulating properties. Administration of Leu- and Trp-BPMs delayed and completely inhibited the amyloidogenic conversion of human prion protein (HuPrP), respectively. We found that each BPM induced the HuPrP to form unique oligomeric nanostructures differing in their biophysical properties, cellular toxicities and response to conformation-specific antibodies. While Leu-BPMs were found to stabilize the oligomers, Trp-BPMs effected transient oligomerization, resulting in the formation of non-toxic, non-fibrillar aggregates. Yet another aromatic residue, Phe, however, accelerated the aggregation process in HuPrP. Molecular insights obtained through MD (molecular dynamics) simulations suggested that each BPM differently engages a conserved Tyr 169 residue at the α2-β2 loop of HuPrP and affects the stability of α2 and α3 helices. Our results demonstrate that this new class of molecules having chemical scaffolds conjugating hydrophobic/aromatic residues could effectively modulate prion aggregation and toxicity.
Kusuma School of Biological Sciences, IIT Delhi, New Delhi, India.
Ankit
A
Srivastava
Department of Chemistry, IIT Delhi, New Delhi, India.
Sakshi
S
Sharma
Department of Chemistry, IIT Delhi, New Delhi, India.
Sandhya
S
Sadanandan
Molecular Sciences Laboratory, National Institute of Immunology, New Delhi, India.
Sakshi
S
Gupta
Kusuma School of Biological Sciences, IIT Delhi, New Delhi, India.
Jasdeep
J
Singh
Molecular Sciences Laboratory, National Institute of Immunology, New Delhi, India.
Sarika
S
Gupta
Department of Chemistry, IIT Delhi, New Delhi, India haridasv@chemistry.iitd.ac.in bkundu@bioschool.iitd.ac.in.
V
V
Haridas
Kusuma School of Biological Sciences, IIT Delhi, New Delhi, India haridasv@chemistry.iitd.ac.in bkundu@bioschool.iitd.ac.in.
Bishwajit
B
Kundu
D000682:Amyloid / Q000737:chemistry*; D000906:Antibodies / Q000737:chemistry; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D049329:Nanostructures / Q000737:chemistry*; D019151:Peptide Library; D057786:Peptidomimetics / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D066329:Protein Aggregates; D017433:Protein Structure, Secondary
D000682:Amyloid; D000906:Antibodies; D019151:Peptide Library; D057786:Peptidomimetics; D011328:Prions; D066329:Protein Aggregates
amyloid; bispidine; cytotoxicity; oligomer; prion; protein misfolding