Chemical Screening Approaches Enabling Drug Discovery of Autophagy Modulators for Biomedical Applications in Human Diseases

Abstract

Autophagy is an intracellular degradation pathway for malfunctioning aggregation-prone proteins, damaged organelles, unwanted macromolecules and invading pathogens. This process is essential for maintaining cellular and tissue homeostasis that contribute to organismal survival. Autophagy dysfunction has been implicated in the pathogenesis of diverse human diseases, and therefore, therapeutic exploitation of autophagy is of potential biomedical relevance. A number of chemical screening approaches have been established for the drug discovery of autophagy modulators based on the perturbations of autophagy reporters or the clearance of autophagy substrates. These readouts can be detected by fluorescence and high-content microscopy, flow cytometry, microplate reader and immunoblotting, and the assays have evolved to enable high-throughput screening and measurement of autophagic flux. Several pharmacological modulators of autophagy have been identified that act either via the classical mechanistic target of rapamycin (mTOR) pathway or independently of mTOR. Many of these autophagy modulators have been demonstrated to exert beneficial effects in transgenic models of neurodegenerative disorders, cancer, infectious diseases, liver diseases, myopathies as well as in lifespan extension. This review describes the commonly used chemical screening approaches in mammalian cells and the key autophagy modulators identified through these methods, and highlights the therapeutic benefits of these compounds in specific disease contexts.

HSPA8/HSC70 in Immune Disorders: A Molecular Rheostat that Adjusts Chaperone-Mediated Autophagy Substrates

“…In light of the vital role of autophagy in immune responses and in general in all metabolic processes of the cell, the pharmacological manipulation of autophagy elements constitutes a unique option of therapeutic intervention [126,127,145,146,147,148,149,150]. In this scheme, HSPA8 represents a hot spot of possible regulation.…”

The Autophagy Pathway: A Critical Route in the Disposal of Alpha 1-Antitrypsin Aggregates That Holds Many Mysteries

“…Interestingly, three drugs: lithium, carbamazepine and valproic acid among the final five hits were previously implicated as inositol-lowering autophagy-inducing agents and have been known to enhance the clearance of aggregate-prone proteins [ 72 , 73 , 74 ]. To go further, chemical modulation of autophagy upon metformin, trehalose or hydrogen sulfide treatments has been shown to have beneficial effects in some liver diseases such as in non-alcoholic fatty liver disease (NAFLD) [ 75 ]. Thus, it would be interesting to test their potential beneficial effects in AATD also ( Table 1 ).…”

Agephagy – Adapting Autophagy for Health During Aging

“…Indeed, many are DNA-damaging agents, such as temozolomide and carboplatin, with negative effects on genome stability (Cheung-Ong et al, 2013). Moreover, as we refine the tools and screening procedures to monitor the autophagic process in healthy and diseased-tissue, it is likely that we will uncover many more autophagy enhancers and inhibitors (Pengo et al, 2018; Panda et al, 2019).…”