Chemical Chaperones Modulate the Formation of Metabolite Assemblies.

Hanaa Adsi,Dana Laor Bar-Yosef,Elvira Haimov,Ehud Gazit,Hamutal Engel,Shon A Levkovich,Massimiliano Meli,Giorgio Colombo,Topaz Kreiser,Luba Simhaev,Shai Karidi-Heller

doi:10.3390/ijms22179172

Abstract

The formation of amyloid-like structures by metabolites is associated with several inborn errors of metabolism (IEMs). These structures display most of the biological, chemical and physical properties of protein amyloids. However, the molecular interactions underlying the assembly remain elusive, and so far, no modulating therapeutic agents are available for clinical use. Chemical chaperones are known to inhibit protein and peptide amyloid formation and stabilize misfolded enzymes. Here, we provide an in-depth characterization of the inhibitory effect of osmolytes and hydrophobic chemical chaperones on metabolite assemblies, thus extending their functional repertoire. We applied a combined in vivo-in vitro-in silico approach and show their ability to inhibit metabolite amyloid-induced toxicity and reduce cellular amyloid content in yeast. We further used various biophysical techniques demonstrating direct inhibition of adenine self-assembly and alteration of fibril morphology by chemical chaperones. Using a scaffold-based approach, we analyzed the physiochemical properties of various dimethyl sulfoxide derivatives and their role in inhibiting metabolite self-assembly. Lastly, we employed whole-atom molecular dynamics simulations to elucidate the role of hydrogen bonds in osmolyte inhibition. Our results imply a dual mode of action of chemical chaperones as IEMs therapeutics, that could be implemented in the rational design of novel lead-like molecules.

Highlights

We examined the effect of four naturally occurring representative chemical chaperones: the DMSO osmolyte, TMAO osmolyte, and the hydrophobic bile acids DCA and UDCA (Figure 1B) [11,31,32]
While amyloid formation has been typically associated with protein misfolding and To elucidate the mode of action of USAFDO-38 and provide a qualitative picture of disease, thethe extension of the canonical to include metabolites has the initial stages of aggregation process in theamyloid absencehypothesis and presence of the inhibitor, opened new avenues in the field of molecular self-assembly and amyloid research
We describe the inhibition by chemical chaperones as their centers of mass was below 0.6 nm

Summary

Introduction

Proteins are highly functionally and structurally diverse biomolecules. Proteins usually obtain a specific conformational state that is considered ‘native’. The folded state of proteins is often only marginally stable [1,2,3]. Physiological, and environmental conditions can induce protein misfolding, resulting in the formation of small aggregation-prone species that tend to self-assemble into supramolecular assemblies [4]. In some cases, these assemblies obtain a fibrillar morphology and a set of canonical biophysical and biochemical traits, which are the hallmarks of amyloids [4,5]

Methods

Results

Conclusion