Structure–Activity Studies on Suramin Analogues as Inhibitors of NAD+‐Dependent Histone Deacetylases (Sirtuins)

Citations Over TimeTop 10% of 2007 papers

Abstract

Suramin is a symmetric polyanionic naphthylurea originally used for the treatment of trypanosomiasis and onchocerciasis. Suramin and diverse analogues exhibit a broad range of biological actions in vitro and in vivo, including, among others, antiproliferative and antiviral activity. Suramin derivatives usually target purinergic binding sites. Class III histone deacetylases (sirtuins) are amidohydrolases that require nicotinamide adenine dinucleotide (NAD(+)) as a cofactor for their catalytic mechanism(.) Deacetylation of the target proteins leads to a change in conformation and alters the activity of the proteins in question. Suramin was reported to inhibit human sirtuin 1 (SIRT1). We tested a diverse set of suramin analogues to elucidate the inhibition of the NAD(+)-dependent histone deacetylases SIRT1 and SIRT2 and discovered selective inhibitors of human sirtuins with potency in the two-digit nanomolar range. In addition, the structural requirements for the binding of suramin derivatives to sirtuins were investigated by molecular docking. The recently published X-ray crystal structure of human SIRT5 in complex with suramin and the human SIRT2 structure were used to analyze the interaction mode of the novel suramin derivatives.

Related Papers

• → Metabolic control by sirtuins and other enzymes that sense NAD+, NADH, or their ratio(2017)203 cited
• → NAD metabolism and sirtuins: Metabolic regulation of protein deacetylation in stress and toxicity(2006)165 cited
• → Free [NADH]/[NAD+] regulates sirtuin expression(2011)48 cited
• → Mutations that Allow SIR2 Orthologs to Function in a NAD+-Depleted Environment(2017)19 cited
• → NAD+ as a Pharmacological Tool to Boost Sirtuin Activity(2016)