Naphthoquinone Tryptophan Hybrids: A Promising Small Molecule Scaffold for Mitigating Aggregation of Amyloidogenic Proteins and Peptides

Abstract

A current challenge faced by researchers is the lack of disease-modifying therapeutics for amyloid formation that is associated with several human diseases. Although the monomeric proteins or peptides involved in various amyloidogenic diseases do not have amino acid sequence homology, there appears to be a structural correlation among the amyloid assemblies, which are responsible for distinct pathological conditions. Here, we review our work on Naphthoquinone Tryptophan (NQTrp) hybrids, a small molecule scaffold that can generically modulate neuronal and non-neuronal amyloid aggregation both in vitro and in vivo. NQTrp reduces the net amyloid load by inhibiting the process of amyloid formation and disassembling the pre-formed fibrils, both in a dose-dependent manner. As a plausible mechanism of action, NQTrp effectively forms hydrogen bonding and hydrophobic interactions, such as π-π stacking, with the vital residues responsible for the initial nucleation of protein/peptide aggregation. This review highlights the effectiveness of the NQTrp hybrid scaffold for developing novel small molecule modulators of amyloid aggregation.

Tryptophan-galactosylamine conjugates inhibit and disaggregate amyloid fibrils of Aβ42 and hIAPP peptides while reducing their toxicity

“…Tryptophan-coated gold and silver nanoparticles have been shown to inhibit both spontaneous and seed-induced aggregation of insulin 82 . Naphthoquinone-tryptophan hybrids displayed promising potential for mitigating the amyloidogenicity of several proteins and peptides 44,45,83 .…”

“…Here we examined this concept by synthesizing tryptophan-galactosylamine hybrid molecules and tested their ability to inhibit the aggregation of Aβ42 and hIAPP. Tryptophan was shown to be highly effective in intercalating the fibrils of various amyloidogenic proteins for inhibiting their aggregations 42 , 44 , 45 , 55 , 56 . Galactose (Gal), one of the most abundant monosaccharide in the human body, plays a vital role in numerous biological processes, modulating and mediating them 57 , 58 .…”

“…Combining the aromatic elements of amino acids and small molecules has also been attempted for amyloid inhibition. For example, a naphthoquinone-tryptophan hybrid was shown to be effective towards various amyloids (including Aβ42, IAPP, Tau, α-Syn) in vitro as well as in vivo [42][43][44][45][46] . However, a major limitation in the drugability of such molecules is their poor solubility in aqueous media [47][48][49] : Attaching a hydrophilic moiety for increasing solubility may enhance the overall therapeutic capacity of a drug 48 .…”

Naphthoquinone–Dopamine Hybrids Inhibit α‐Synuclein Aggregation, Disrupt Preformed Fibrils, and Attenuate Aggregate‐Induced Toxicity

“…[42] The other element of the designed hybrid molecules, NQ, was chosen because quinone exhibitsv arious biological properties and its derivatives, for example NQTrp, were shown to modulate aggregation of several amyloidogenic proteins associated with various proteinopathies, including PD. [27,43,44] The modeo fa ction of NQTrp with an amyloidogenic protein likely occurs through p-p interaction between the aro-matic moiety of Tryptophan anda romatic amino acid of the protein, while the quinone element interferes with the process aggregation, thus resulting in inhibition of amyloid formation. [44][45][46][47] These activities of NQ derivatives and DA prompted us to conjugate them and we hypothesized that the aromatic moiety of DA in the hybrid molecules NQDA and Cl-NQDA will bind the aromatic residues of a-Syn and intercalate within the b-sheets of the protein, whereas the NQ moiety together with the two hydroxyl groups of DA will hindert he a-Syn self-aggregation process to inhibit amyloid formation.…”

“…[27,43,44] The modeo fa ction of NQTrp with an amyloidogenic protein likely occurs through p-p interaction between the aro-matic moiety of Tryptophan anda romatic amino acid of the protein, while the quinone element interferes with the process aggregation, thus resulting in inhibition of amyloid formation. [44][45][46][47] These activities of NQ derivatives and DA prompted us to conjugate them and we hypothesized that the aromatic moiety of DA in the hybrid molecules NQDA and Cl-NQDA will bind the aromatic residues of a-Syn and intercalate within the b-sheets of the protein, whereas the NQ moiety together with the two hydroxyl groups of DA will hindert he a-Syn self-aggregation process to inhibit amyloid formation. Ap revious report observed that tyramine, which differs from DA only by a hydrogen replacing ah ydroxyl group, exhibited less inhibitory activity than DA towards a-Syn due to aloss of electrostatic interactions with the two negatively charged groups of the NAC region in a-Syn.…”