Emerging roles of SIRT1 activator, SRT2104, in disease treatment

Abstract

Silent information regulator 1 (SIRT1) is a NAD⁺-dependent class III deacetylase that plays important roles in the pathogenesis of numerous diseases, positioning it as a prime candidate for therapeutic intervention. Among its modulators, SRT2104 emerges as the most specific small molecule activator of SIRT1, currently advancing into the clinical translation phase. The primary objective of this review is to evaluate the emerging roles of SRT2104, and to explore its potential as a therapeutic agent in various diseases. In the present review, we systematically summarized the findings from an extensive array of literature sources including the progress of its application in disease treatment and its potential molecular mechanisms by reviewing the literature published in databases such as PubMed, Web of Science, and the World Health Organization International Clinical Trials Registry Platform. We focuses on the strides made in employing SRT2104 for disease treatment, elucidating its potential molecular underpinnings based on preclinical and clinical research data. The findings reveal that SRT2104, as a potent SIRT1 activator, holds considerable therapeutic potential, particularly in modulating metabolic and longevity-related pathways. This review establishes SRT2104 as a leading SIRT1 activator with significant therapeutic promise.

Keywords: Clinical trials; Disease treatment; Preclinical research; SIRT1; SRT2104.

Figure 1

Chemical structure of a classical SIRT1 activator. (A) Natural SIRT1 activator. (B) First generation synthesized SIRT1 activator. (C) Second generation synthesized SIRT1 activator.

Figure 2

Interaction of SRT2104 with SIRT1. (A) Detailed binding profile of SRT2104 to SIRT1. (B) Illustrative representation of the molecular interaction between SRT2104 and SIRT1. Molecular docking simulations were conducted utilizing AutoDock software to model the interaction. A grid box measuring 126 Å in each dimension was established, with a grid point spacing of 0.375 Å. During the simulations, the ligands were allowed to flex, whereas the protein's amino acid residues were held fixed. The calculated binding energy served as a measure of affinity. Visualization of the interaction was enhanced using PyMol and Discover Studio, revealing that SRT2104 occupies the hydrophobic pocket of SIRT1. The amine group of SRT2104 forms hydrogen bonds with Gly269, Gln320, and Glu512 in the SIRT1 structure. Additionally, an oxygen atom of SRT2104 engages in a hydrogen bond with ARG282, contributing to the stability of the interaction. Hydrophobic contacts are further augmented by interactions between SRT2104 and SIRT1's Pro271, Arg282, Phe312, Lys314, and Phe321, including Pi-Pi stacking and alkyl interactions. Van der Waals forces involving Ile270, Ile279, Leu283, Ile316, Phe388, Ile510, and Thr511 also play a vital role in sustaining the interaction's stability.

Figure 3

Schematic representation of the molecular mechanisms mediated by SRT2104. SRT2104, through the activation of SIRT1, orchestrates a network of molecular pathways, including P53, STAT3, ZKSCANS, AMPK, GR, GSK3β/PTEN, NF-κB, β-catenin/Runx2, MAPK, Smad7, FOXO, and TORC1. These interactions collectively contribute to the amelioration of conditions such as lung injury, diabetic vascular complications, diabetic nephropathy, cognitive impairments associated with diabetes, musculoskeletal disorders, brain ischemia–reperfusion injury, Parkinson's disease (PD) neurodegeneration, and optic nerve damage. Key: "→" denotes activation or promotion, "⊥" indicates inhibition, "red arrow up" signifies upregulation, "green arrow down" signifies downregulation, and "Ac" refers to deacetylation.

Figure 4

Overview of the potential effects of SRT2104 on various organ systems. The diagram illustrates the compound's impact on key physiological processes across different tissues. “↓”denotes a decrease or impairment, while “↑” signifies an increase or enhancement. This figure summarizes the multifaceted pharmacological actions of SRT2104, suggesting its potential therapeutic applications.