Triptolide Analogs as Anti-Inflammatory Agents

Emory University
posted on 07/07/2009

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Applications

Novel small molecule therapeutics for the treatment of inflammatory diseases, autoimmune disorders, and transplant rejection.

Highlights

• Small molecule therapeutics with low toxicity.
• Analogs were shown to bind directly to nuclear factor kappa B (NFkB).

Technical Summary

Herbal extracts from the perennial vine, Tripterygium Wilfordii hook F (TWHF), have been used for medicinal purposes for thousands of years. Ancient Chinese practitioners used extracts derived from the roots of TWHF for the treatment of rheumatoid arthritis, swelling, skin infections, leprosy, fever, boils, and chills. More recently, scientists have shown that triptolide, the active compound in TWHF extracts, can suppress an overactive immune system, prevent inflammation, and kill cancer cells. However, parts of TWHF are extremely pas reflected in two of its Chinese folk names "Walk Seven Steps and Die Vine" and intestine extracts have seen limited use in the clinic and it comes as no surprise that purified triptolide is fatally toxic when administered to mice even in small quantities.

TWHF for the treatment of rheumatoid arthritis, swelling, skin infections, leprosy, fever, boils, and chills.  More recently, scientists have shown that triptolide, the active compound in TWHF extracts, can suppress an overactive immune system, prevent inflammation, and kill cancer cells. However, parts of TWHF are extremely poisonous, as reflected in two of its Chinese folk names - "Walk Seven Steps and Die Vine" and "Intestine Breaking Plant." As a result, TWHF extracts have seen limited use in the clinic and it comes as no surprise that purified triptolide is fatally toxic when administered to mice even in small quantities. 

Dr. Dennis Liotta and colleagues have developed novel analogs of triptolide and initial in vivo studies suggest the lead compound is non-toxic even when administered at three hundred times the dose at which triptolide is fatal to mice.  In a carrageenan-induced mouse paw inflammation model, once daily administration of the lead compound injected interperitoneally resulted in significantly reduced paw swelling and decreased inflammatory cytokine transcription compared to controls.  Like triptolide, the analogs were shown in binding assays to bind directly to nuclear factor kappa B (NFkB) and interfere with NFkB binding to its DNA consensus sequence.  At equivalent concentrations, triptolide was only thirty percent as effective as the analog at inhibiting NFkB binding to DNA. 

Developmental Stage & Potential Market

• Additional in vivo efficacy studies are being carried out in multiple inflammatory disease models (including rheumatoid arthritis) and more extensive toxicology studies are in progress or planned.
• Inflammatory diseases affect an estimated 80+ million people globally and it is projected that by 2009, more than $51 billion in worldwide drug sales will be for drugs that treat inflammatory diseases (including arthritis and asthma).