Phenylalanine-based fibrillar systems.

Phenylketonuria (PKU) is an inborn metabolic disorder characterized by excess accumulation of phenylalanine (Phe) and its fibril formation, resulting in progressive intellectual disability. Several research groups have approached from various directions to understand the formation of toxic amyloid fibrils from the essential amino acid Phe. Different parameters like the nature of the solvent, pH, Phe concentration, temperature, etc. influence the fibril formation kinetics. In this article, we have summarized all major findings regarding the formation of Phe-based fibrils in aqueous and organic media and discussed how non-covalent interactions are involved in the self-assembly process using spectroscopic and microscopic techniques. The toxicity of Phe-based fibrils is compared with other neurodegenerative peptides. It is noted that the Phe-based fibrils can also induce various globular proteins into toxic fibrils. Later, we discuss the different approaches to inhibit fibril formation and reduce its toxicity. The presence of polyphenolic compounds, drugs, amino acids, nanoparticles, metal ions, crown ethers, and others showed a remarkable inhibitory effect on fibril formation. To the best of our knowledge, this is the first-ever etymological analysis of the Phe-fibrillar system and its inhibition to create a strong database against PKU.

Probing Molecular Chirality on the Self-Assembly and Gelation of Naphthalimide-Conjugated Dipeptides.

In this work, 1,8-naphthalimide (NMI)-conjugated three hybrid dipeptides constituted of a ß-amino acid and an α-amino acid have been designed, synthesized, and purified. Here, in the design, the chirality of the α-amino acid was varied to study the effect of molecular chirality on the supramolecular assembly. Self-assembly and gelation of three NMI conjugates were studied in mixed solvent systems [water and dimethyl sulphoxide (DMSO)]. Interestingly, chiral NMI derivatives [NMI-ßAla-lVal-OMe (NLV) and NMI-ßAla-dVal-OMe (NDV)] formed self-supported gels, while the achiral NMI derivative [NMI-ßAla-Aib-OMe, (NAA)] failed to form any kind of gel at 1 mM concentration and in a mixed solvent (70% water in DMSO medium). Self-assembly processes were thoroughly investigated using UV-vis spectroscopy, nuclear magnetic resonance (NMR), fluorescence, and circular dichroism (CD) spectroscopy. A J-type molecular assembly was observed in the mixed solvent system. The CD study indicated the formation of chiral assembled structures for NLV and NDV, which were mirror images of one another, and the self-assembled state by NAA was CD-silent. The nanoscale morphology of the three derivatives was studied using scanning electron microscopy (SEM). In the case of NLV and NDV, left- and right-handed fibrilar morphologies were observed, respectively. In contrast, a flake-like morphology was noticed for NAA. The DFT study indicated that the chirality of the α-amino acid influenced the orientation of π-π stacking interactions of naphthalimide units in the self-assembled structure that in turn regulated the helicity. This is a unique work where molecular chirality controls the nanoscale assembly as well as the macroscopic self-assembled state.