Novel drug discovery strategies for gout

The increasing prevalence of gout has been accompanied by a growing number of patients intolerant to or with disease refractory to available urate-lowering therapies. These difficult-to-treat patients currently represent about 3 - 5% of people with gout in Europe and the United States, which highlights the need for emerging treatments to effectively lower urate levels.

In this review, the authors describe the putative pharmacological targets to lower urate levels. Furthermore, the authors discuss various strategies used to discover novel molecules or to improve available drugs used to treat gout.

Major advances in our understanding of urate renal transport from in vitro, animal and genetic studies could lead to the development of novel uricosuric drugs. Targeting one or several urate transporters such as urate transporter 1, organic anion transporter 4 and 10 and glucose transporter 9 is promising. Moreover, design of small molecules capable of blocking the site activity of enzymes other than xanthine oxidase and involved in the purine pathway could generate novel hypouricemic drugs. Finally, polyethylene glycol (PEGylation) can significantly extend the biological half-life of drugs and reduce antigenicity and immunogenicity of proteins. The technology has been successfully applied to an uricase (pegloticase), but the drug was immunogenic in some patients. Strategies to decrease the immunogenicity of a PEG-uricase are important for developing next-generation uricase.