Defensin-based therapeutic peptide design in attenuating V30M TTR-induced Familial Amyloid Polyneuropathy.

Unlabelled: In the present study, we aimed to formulate an effective therapeutic candidate against V30M mutant transthyretin (TTR) protein to hinder its pathogenic misfolding. Nicotiana alata Defensin 1 (NaD1) Antimicrobial Peptide (AMP) was availed due to its tendency to aggregate, which may compete for aggregation-prone regions of pathogenic TTR protein. Based on NaD1's potential to bind to V30M TTR, we proposed NaD1-derived tetra peptides: CKTE and SKIL to be initial therapeutic candidates. Based on their association with mutant TTR protein, CKTE tetra peptide showed considerable interaction and curative potential as compared to SKIL tetra peptide. Further analyses from discrete molecular dynamics simulation corroborate CKTE tetra peptide's effectiveness as a 'beta-sheet breaker' against V30M TTR. Various post-simulation trajectory analyses suggested that CKTE tetra peptide alters the structural dynamics of pathogenic V30M TTR protein, thereby potentially attenuating its beta-sheets and impeding its aggregation. Normal mode analysis simulation corroborated that V30M TTR conformation is altered upon its interaction with CKTE peptide. Moreover, simulated thermal denaturation findings suggested that CKTE-V30M TTR complex is more susceptible to simulated denaturation, relative to pathogenic V30M TTR; further substantiating CKTE peptide's potential to alter V30M TTR's pathogenic conformation. Moreover, the residual frustration analysis augmented CKTE tetra peptide's proclivity in reorienting the conformation of V30M TTR. Therefore, we predicted that the tetra peptide, CKTE could be a promising therapeutic candidate in mitigating the amyloidogenic detrimental effects of V30M TTR-mediated familial amyloid polyneuropathy (FAP).

Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03646-4.