Therapeutic perspectives on PDE4B inhibition in adipose tissue dysfunction and chronic liver injury

Abstract

Introduction: Chronic liver disease (CLD) is a complex disease associated with profound dysfunction. Despite an incredible burden, the first and only pharmacotherapy for metabolic-associated steatohepatitis was only approved in March of this year, indicating a gap in the translation of preclinical studies. There is a body of preclinical work on the application of phosphodiesterase 4 inhibitors in CLD, none of these molecules have been successfully translated into clinical use.

Areas covered: To design therapies to combat CLD, it is essential to consider the dysregulation of other tissues that contribute to its development and progression. As such, proper therapies must combat this throughout the body rather than focusing only on the liver. To detail this, literature characterizing the pathogenesis of CLD was pulled from PubMed, with a particular focus placed on the role of PDE4 in inflammation and metabolism. Then, the focus is shifted to detailing the available information on existing PDE4 inhibitors.

Expert opinion: This review gives a brief overview of some of the pathologies of organ systems that are distinct from the liver but contribute to disease progression. The demonstrated efficacy of PDE4 inhibitors in other human inflammatory diseases should earn them further examination for the treatment of CLD.

Keywords: Adipose; alcohol; chronic liver disease; liver fibrosis; obesity; phosphodiesterase.

Figure 1.

The involvement of other organ systems in the pathogenesis of chronic liver injury. Created with BioRender.com.

Figure 2.

Role of PDE4 in FA metabolism in the liver. Created with BioRender.com.

Figure 3.

The interaction between cyclic AMP signaling pathways in lymphocytes and the expression of pro-inflammatory signaling pathways. Created with BioRender.com.

Figure 4.

Role of PDE4 subcellular localization in T-Cell activation. Adapted with permission from Abrahamsen H, Baillie G, Ngai J, et al. TCR- and CD28-Mediated Recruitment of Phosphodiesterase 4 to Lipid Rafts Potentiates TCR Signaling1. The Journal of Immunology. 2004;173(8):4847–4858. Created with BioRender.com.

Figure 5.

KVA-D88 loaded nanoparticles alleviate alcohol-induced liver injury and inflammation after systemic administration into mice. (A) Representative microscopic pictures of IHC staining for PDE4B. PDE4B expression was upregulated in mice liver by alcohol diet. Scale bars (120×), 100 μm. (B) Representative microscopic pictures of H&E staining of mice liver tissue. Scale bars (20×), 200 μm. (C,D) Mice plasma AST and ALT levels. (E,F) Mice hepatic mRNA expression level of TNF-α and IL-1β. Results are presented as the mean ± SD (n = 3). * p < 0.05, ** p < 0.01 and *** p < 0.005. Adapted from Ma J, Kumar, V., and R.I. Mahato. Nanoparticle Delivery of Novel PDE4B Inhibitor for the Treatment of Alcoholic Liver Disease. Pharmaceutics. 2022;14(9):1894 under CC-BY license.

Figure 6.

PDE4B selective inhibitor captures the C-terminal CR3 by novel binding mode A. Domain architecture for full-length PDE4 and the crystallization construct (PDE4B CAT + CR3). B-D. A-33 (cyan) interaction with catalytic domain (blue) and CR3 (yellow). B. “P-clamp” and “Q-switch.” C. Hydrogen bonding network bridging CR3 and A-33 carboxylic acid. D. Hydrophobic interactions with A-33 thiophene. Atom coloring – Oxygen (red), Nitrogen (blue), Carbon (cyan), Chloride (green), and Sulfur (yellow). Metals are shown as large spheres (Mg²⁺ - green and Zn²⁺ - silver) and waters are shown as small red spheres. Hydrogen-bonds are represented by black dashed lines. PDB: 4MYQ. Adapted from Fox D, Burgin AB, Gurney ME. Structural basis for the design of selective phosphodiesterase 4B inhibitors. Cellular Signalling. 2014 2014/03/01/;26(3):657–663 under CC-BY-NC-SA license.

Figure 7.

Binding modes of phenoxybenzoxaborole PDE4B inhibitors at the catalytic domain. A. Crystal structure of AN2898 (cyan), bound at the active site of PDE4B catalytic domain, is superimposed on to that of AMP (white). The crystal structure of AMP complexed with PDE4 was obtained from a protein databank,1PTW. Color code: blue for carbon in AN2898/PDE4B structure and white for AMP/PDE4B structure, red for oxygen, and dark blue for nitrogen atoms, and B. Docking model of AN4800 (green) at the active site of PDE4B catalytic domain. Color code: blue for protein carbon and cyan for ligand carbon atoms, red for oxygen, and dark blue for nitrogen atoms. Adapted from Freund YR, Akama T, Alley MRK, et al. Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center. FEBS Letters. 2012;586(19):3410–3414 under CC-BY-NC-ND license.