Pharmaceutical Strategies to Improve Druggability of Potential Drug Candidates in Nonalcoholic Fatty Liver Disease Therapy

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become globally prevalent and is the leading cause of chronic liver disease. Although NAFLD is reversible without medical intervention in the early stage, the condition could be sequentially worsened to nonalcoholic steatohepatitis (NASH) and, eventually, cirrhosis and hepatic cancer. The progression of NAFLD is related to various factors such as genetics, pre-disposed metabolic disorders, and immunologic factors. Thankfully, to date, there have been accumulating research efforts and, as a result, different classes of potent drug candidates have been discovered. In addition, there have also been various attempts to explore pharmaceutical strategies to improve the druggability of drug candidates. In this review, we provided a brief overview of the drug candidates that have undergone clinical trials. In the latter part, strategies for developing better drugs are discussed.

Keywords: cirrhosis; fibrosis; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; strategies.

Figure 1

Schematic representation of crosstalk between the organs and major regulatory pathways in NAFLD. A group of NAFLD drug candidates (e.g., SGLT2 inhibitors, GLP-1R agonists, PPAR agonists, FGF19 and FGF21 analogs, and FXR agonists) have been developed and have undergone (or are still ongoing) clinical trials. The action mechanisms of these compounds involve various and multiple pathways related to: (1) regulation of glucose and lipid homeostasis in the network of adipose tissues, the brain, pancreas, and liver; (2) modulating de novo lipogenesis, lipolysis, and β-oxidation of free fatty acids; (3) reducing food intake (indicated by downward arrow) and body weight; (4) improving insulin resistance (increased insulin sensitivity indicated by upward arrow) in liver and adipose tissues; and (5) regulating bile acid production (CYP7α1, cholesterol 7-α-hydroxylase; FFA, free fatty acid; FGF, fibroblast growth factors; FGFR, fibroblast growth factor receptor; FXR, farnesoid X receptor; GLP-1R, glucagon-like peptide-1 receptor; PPAR, peroxisome proliferator-activator receptor; KBL, β-klotho; SGLT2, sodium-glucose co-transporter 2; SREBP-1, sterol regulatory element-binding protein-1; TGs, triglycerides; VLDL, very low density lipoprotein).

Figure 2

Schematic diagram of the pharmaceutical strategies to make “better drugs” for NAFLD therapy. To enhance the therapeutic efficacy of NALFD drug candidates, the three strategies widely explored include (A) the development of multi-receptor agonists, (B) engineering long-acting derivatives, and (C) devising ligand-decorated nanoparticle-based hepatic targeting systems. The increase of plasma half-life could be accomplished by conjugation of polymers (e.g., PEG) or fusion of IgG Fc or human serum albumin (HSA). The latter enables the drug compound to go through FcRn-mediated recycling. Liver targeting could be achieved by utilizing ligands selective for receptors expressed on the membranes of liver-composing cells (ASGPR, asialoglycoprotein; FcRn, neonatal Fc receptor; FGFR, fibroblast growth factor receptor; GIPR, glucose-dependent insulinotropic polypeptide receptor; GCGR, glucagon receptor; GLP-1R, glucagon-like peptide-1 receptor; HA-R: hyaluronan receptor; HSA, human serum albumin; HSCs, hepatic stellate cells; LDLR, low-density lipoprotein receptor; LSECs, liver sinusoidal endothelial cells; MR, mannose receptor; PEG, polyethylene glycol; PPAR, peroxisome proliferator-activator receptor; RBPR, retinol-binding protein receptor).