The Yin and Yang of the Natural Product Triptolide and Its Interactions with XPB, an Essential Protein for Gene Expression and DNA Repair

Abstract

Triptolide, a bioactive diterpene tri-epoxide extracted from Tripterygium wilfordii Hook F (TWHF), exhibits notable pharmacological activities, including anti-inflammatory, immunosuppressive, antifertility, and anticancer effects. Despite its promising therapeutic potential, clinical applications of triptolide are significantly limited by its poor water solubility and substantial toxicity, particularly hepatotoxicity, nephrotoxicity, and cardiotoxicity. These toxic effects are difficult to separate from many of its desired therapeutic effects, the Yin and Yang of triptolide applications. Triptolide's therapeutic and toxic effects are linked to its inhibitory interactions with XPB, a DNA helicase essential for transcription by RNA polymerase II (RNAPII) and nucleotide excision repair (NER). By irreversibly binding to XPB, triptolide inhibits its ATPase activity, leading to global repression of transcription and impaired NER, which underlies its cytotoxic and antitumor properties. Recent developments, including triptolide prodrugs such as Minnelide and derivatives like glutriptolides, aim to enhance its pharmacokinetic properties and reduce toxicity. This review critically examines triptolide's chemical structure, therapeutic applications, toxicological profile, and molecular interactions with XPB and other protein targets to inform future strategies that maximize therapeutic efficacy while minimizing adverse effects.

Keywords: anticancer drug; autoimmune disease; hepatotoxicity; inflammation; transcription.

Figure 1

Structure of triptolide. The oxygen atoms and hydroxide group are highlighted in red.

Figure 2

Three water-soluble triptolide derivatives.

Figure 3

Schematic summary of triptolide potential medical applications.

Figure 4

Mechanisms of triptolide toxicity.

Figure 5

Models of triptolide bound to human XPB and DCTPP1. (Left): triptolide (ball and sticks with O atoms in red) covalently docked at residue Cys342 (yellow stick) of human XPB (gray ribbons) (PDB ID: 7NVV); (middle): ADP (sticks with N atoms in blue and O atoms in red)-BF3 (green sticks) bound to human XPB (gray ribbons) (PDB ID: 7NVV); (right): Superimposition of triptolide (light orange sticks with O atoms in red and H atoms in white) bound to human DCTPP1 (PDB ID: 7MU5) (monomer A in green cartoon while monomer B in lime ribbons) over dCMP (gray sticks with N atoms in blue and O atoms in red) bound to M. musculus dCTPase (PDB ID: 6SQW) (monomer A in gray cartoon while monomer B in gray ribbons). Bright green dashed lines indicate H-bond interactions. The Walker A motif of human XPB is highlighted by a magenta color.