Promising drug discovery strategies for sirtuin modulators: what lessons have we learnt?

ABSTRACT

Introduction

Sirtuins, NAD-dependent protein deacetylases, require NAD⁺ for enzymatic activity. Recent research has indicated that sirtuins have a key role in the regulation of gene expression, the cell cycle, apoptosis, neurodegeneration and several age-related diseases. In mammals, there are seven sirtuin isoforms (SIRT-1-7) that catalyze specific lysine substrate deacetylation.

Areas Covered

This review explains the current information on the structure, function and importance of sirtuin modulators. It also explores the possible therapeutic applications of sirtuin modulators and related small molecules in the context of various diseases.

Expert opinion

Sirtuin’s modulators open a new area of research for targeting pathological conditions. Sirtuin modulators, through their targeted function, may provide a possible tool for the amelioration of various diseases. However, the search of activators/inhibitors for sirtuins needs further research. The structural elucidation of sirtuins will create an understanding for the development of isoform-specific selective modulators. This could be a useful tool to determine the functions of individual sirtuins as potential therapeutic agents.

KEYWORDS:

• Sirtuins
• sirtuin modulators
• sirtuin-activating compounds
• aging
• nad⁺ boosting molecules
• resveratrol

Article highlights

• Sirtuins, classified as NAD⁺-dependent histone deacetylases, regulate several metabolic pathways, gene expression, cell cycle, and apoptosis in both prokaryotes and eukaryotes.

• Mammals express seven sirtuin isoforms (SIRT-1–7) which differ in their subcellular localization and substrate specificities.

• Sirtuins provide possible targets to treat various diseases such as neurological diseases, cardiovascular diseases, and cancer.

• Small-molecule sirtuin activators/inhibitors have proven to be effective therapeutic interventions.

• Sirtuin activators or inhibitors might provide an important insight into the pathophysiology of various diseases.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was funded by a Science and Engineering Research Board (SERB) grant (EMR/2016/006470) awarded to SI Rizvi. The Department of Biochemistry of the University of Allahabad is supported by a Fund for Improvement of S&T Infrastructure (FIST) grant from the Department of Science & Technology (DST), the Government of India. and a Special Assistance Programme Departmental Research Support (SAP DRS) grant from the University Grants Commission. G Garg is a recipient of a National Post-Doctoral Fellowship (NPDF) grant from the DST-SERB, of the Government of India (PDF/2019/001452). Furthermore, S Singh is recipient of a Senior Research Fellowship from Indian Council of Medical Research, India((3/1/2(3)/GER/2018-NCD-II)). Financial funding from Department of Biotechnology, Govt of India under the ‘Research Resources, Service Facilities and Platforms’ is also gratefully acknowledged.