Aza-Residue Modulation of Cyclic D,l-α-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity

Maram Habashi, Pradeep S. Chauhan, Suresh Vutla, Sudipta Senapati, Mykhailo Diachkov, Ali EL-Husseini, Brigitte Guérin, William D. Lubell, Shai Rahimipour

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Transient soluble oligomers of amyloid-β (Aβ) are considered among the most toxic species in Alzheimer’s disease (AD). Soluble Aβ oligomers accumulate early prior to insoluble plaque formation and cognitive impairment. The cyclic d,l-α-peptide CP-2 (1) self-assembles into nanotubes and demonstrates promising anti-amyloidogenic activity likely by a mechanism involving engagement of soluble oligomers. Systematic replacement of the residues in peptide 1 with aza-amino acid counterparts was performed to explore the effects of hydrogen bonding on propensity to mitigate Aβ aggregation and toxicity. Certain azapeptides exhibited improved ability to engage, alter the secondary structure, and inhibit aggregation of Aβ. Moreover, certain azapeptides disassembled preformed Aβ fibrils and protected cells from Aβ-mediated toxicity. Substitution of the l-norleucine3 and d-serine6 residues in peptide 1 with aza-norleucine and aza-homoserine provided, respectively, nontoxic [azaNle3]-1 (4) and [azaHse6]-1 (7), that significantly abated symptoms in a transgenic Caenorhabditis elegans AD model by decreasing Aβ oligomer levels.

Original languageEnglish (US)
Pages (from-to)3058-3072
Number of pages15
JournalJournal of medicinal chemistry
Issue number4
StatePublished - Feb 23 2023
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


Dive into the research topics of 'Aza-Residue Modulation of Cyclic D,l-α-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity'. Together they form a unique fingerprint.

Cite this