4-Methylumbelliferone, an hyaluronan synthase inhibitor, prevents the development of oncological, inflammatory, degenerative and autoimmune disorders

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Abstract

In present review we consider numerous experiments on tissue cultures, animal models of diseases and the first clinical studies providing the prospects of creating new drugs based on 4-MU. We believe that along with many receptors and transcription factors, the main pharmacological target of 4-MU is the hyaluronan synthase, which produces the main component of the extracellular matrix, glycosaminoglycan, hyaluronic acid (HA). The pharmacological effects of 4-MU in oncological, autoimmune, degenerative and hypercompensated regenerative processes (fibrosis, scarring) are associated with inhibition of HA synthesis. Clinical drugs based on 4-MU will be the first in the class for the treatment of a wide range of diseases.

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About the authors

V. V. Fedorova

Skolkovo Institute of Science and Technology

Email: y.kotelevtsev@skoltech.ru
Russian Federation, 121205 Moscow

A. Tsitrina

Ben-Gurion University of the Negev

Email: y.kotelevtsev@skoltech.ru
Israel, 8410501 Be’er Sheva

N. Halimani

Skolkovo Institute of Science and Technology

Email: y.kotelevtsev@skoltech.ru
Russian Federation, 121205 Moscow

Y. V. Kotelevtsev

Skolkovo Institute of Science and Technology

Author for correspondence.
Email: y.kotelevtsev@skoltech.ru
Russian Federation, 121205 Moscow

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2. Rice. 1. Scheme of HA synthesis with the participation of hyaluronan synthase. UDP-GlcNAc – uridine-5′-diphosphate-N-acetylglucosamine; GlcA – glucuronic acid

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3. Fig. 2. Proposed mechanism of action of 4-MU on HA synthesis. a – The diagram represents the normal pathway of HA synthesis. b – The diagram shows the substitution of UDP by the 4-MU pool, as a result of which HAS cannot synthesize HA. GlcNAc – N-acetylglucosamine; GlcA – glucuronic acid; 4-MU – 4-methylumbelliferone; UDP – uridine-5′-diphosphate; UGT – uridine-5′-diphosphate-glucuranosyltransferase; UDP-GlcNAc – uridine-5′-diphosphate-N-acetylglucosamine; UDP-GlcA – uridine-5′-diphosphate-glucuronic acid; HAS – hyaluronan synthase; GlcNAc-β(1,4)-GlcA – N-acetyl-glucosamine-β(1,4)-glucuronic acid. Figure taken from the article Nagy et al., 2015 [26]

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4. Fig. 3. Schematic representation of the pathways of inhibition of HA synthesis by 4-MU. 4-MU acts in several ways: either by depletion of the HA precursor, UDP-glucuronic acid; or by inhibition of expression of the gene encoding HAS2 in the nucleus; or by indirect inhibition of hyaluronan synthase activity. 4-MU – 4-methylumbelliferone; HAS2 – hyaluronan synthase. Figure taken from review by Vitale et al. [1]

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