Natural Products as Modulators of Sirtuins.

Wolfgang Sippl,Fidele Ntie-Kang,Berin Karaman Mayack

doi:10.3390/molecules25143287

Abstract

Natural products have been used for the treatment of human diseases since ancient history. Over time, due to the lack of precise tools and techniques for the separation, purification, and structural elucidation of active constituents in natural resources there has been a decline in financial support and efforts in characterization of natural products. Advances in the design of chemical compounds and the understanding of their functions is of pharmacological importance for the biomedical field. However, natural products regained attention as sources of novel drug candidates upon recent developments and progress in technology. Natural compounds were shown to bear an inherent ability to bind to biomacromolecules and cover an unparalleled chemical space in comparison to most libraries used for high-throughput screening. Thus, natural products hold a great potential for the drug discovery of new scaffolds for therapeutic targets such as sirtuins. Sirtuins are Class III histone deacetylases that have been linked to many diseases such as Parkinson`s disease, Alzheimer’s disease, type II diabetes, and cancer linked to aging. In this review, we examine the revitalization of interest in natural products for drug discovery and discuss natural product modulators of sirtuins that could serve as a starting point for the development of isoform selective and highly potent drug-like compounds, as well as the potential application of naturally occurring sirtuin inhibitors in human health and those in clinical trials.

Highlights

Today, the journey of a drug, starting from the discovery of the first-compound active in vitro to the shelves in a drug store, takes about 13 years and costs over 1.5 billion dollars [1]
Another concern about using natural products in drug discovery approaches was related with the technical problems such as purification, structure elucidation of the active ingredients from extracts, the need for repeated isolation of the active ingredient to be able to have enough for biochemical assays, and developing a synthetic method to be able to produce the active ingredient during pharmaceutical manufacture [14]
Sirtuins are an important class of histone deacetylases, which are involved in NAD+-dependent deacetylation reactions

Summary

Introduction

The journey of a drug, starting from the discovery of the first-compound active in vitro to the shelves in a drug store, takes about 13 years and costs over 1.5 billion dollars [1]. There was a belief in the pharmaceutical industry that NPs were not compatible with the assays implemented in HTS directed at macromolecular targets [23] Another concern about using natural products in drug discovery approaches was related with the technical problems such as purification, structure elucidation of the active ingredients from extracts, the need for repeated isolation of the active ingredient to be able to have enough for biochemical assays, and developing a synthetic method to be able to produce the active ingredient during pharmaceutical manufacture [14]. The relevance of medicinal plants or herbs commonly used by different cultures as part of their traditional medicine needs to be explored more thoroughly

Sirtuins as Therapeutic Targets

Natural Product Modulators of Sirtuins

Stilbenoids

Chromone-Derived Natural Products

Tanikolide

Tanikolide Dimer from the Madagascan Marine Cyanobacterium Lyngbya majuscula

Bichalcones from the African Medicinal Plant Lyngbya majuscula

Findings

Conclusions