New drug targets for the treatment of gout arthritis: what’s new?

ABSTRACT

Introduction

Gout arthritis (GA) is an intermittent inflammatory disease affecting approximately 10% of the worldwide population. Symptomatic phases (acute flares) are timely spaced by asymptomatic periods. During an acute attack, redness, joint swelling, limited movement, and excruciating pain are common symptoms. However, the current available therapies are not fully effective in reducing symptoms and offer numerous side effects. Therefore, unveiling new drug targets and effector molecules are required in developing novel GA therapeutics.

Areas covered

This review discusses the pathophysiological mechanisms of GA and explores potential pharmacological targets to ameliorate disease outcome. In addition, we listed promising pre-clinical studies demonstrating effector molecules with therapeutical potential. Among those, we emphasized the importance of natural products, including traditional Chinese medicine formulas and their multitarget mechanisms of action.

Expert opinion

In our search, we observed that there is a massive gap between pre-clinical and clinical knowledge. Only a minority (4.4%) of clinical trials aimed to intervene by applying natural products or current hot targets described herein. In this sense, we envisage four possibilities for GA therapeutics, which include the repurposing of existing therapies, ALX/FPR2 agonism for improvement in disease outcome, the use of multitarget drugs (e.g. natural products), and targeting the neuroinflammatory component of GA.

KEYWORDS:

• natural products
• antioxidants
• multitargeting drug
• specialized pro-resolving lipid mediators
• microbiota
• neuroimmune interactions
• drug repurposing

Article highlights

• Current therapies for GA are not fully effective in controlling its symptoms.

• The side-effects of available drugs are associated with treatment discontinuance or are not safe for patients with comorbidity.

• There is a huge gap in translational studies from pre-clinical to clinical research.

• In this review, we highlight 15 mechanism-based drug targets for GA prevention, incidence, and treatment.

• Lipid mediator production and signaling are effective targets for GA therapeutics: blockage of pro-inflammatory mediators and endogenous production of specialized pro-resolving mediators (SPMs) or pharmacological treatment restore tissue homeostasis in monosodium urate (MSU)-induced animal models of GA.

• Natural products with antioxidant and multitarget mechanisms are highly effective in ameliorate MSU-induced GA in pre-clinical studies, thus are suitable candidates for drug development or repurposing.

Declaration of interests

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Author contributions

All authors contributed significantly to the writing and conception of this review article as well as approved the final version of the manuscript.

Acknowledgments

The authors thank Rachel Arredondo from Boston Children’s Hospital for proof-reading the manuscript.

Additional information

Funding

This work was supported by a Brazilian grant from the Department of Science and Technology from the Science, Technology and Strategic Inputs Secretariat of the Ministry of Health [Decit/SCTIE/MS, Brazil] intermediated by the National Council for Scientific and Technological Development [CNPq, Brazil] with support of Araucária Foundation and State Health Secretariat, Paraná [SESA−PR, Brazil; PPSUS Grant agreement 041/2017, protocol 48.095]. We also have the support of Brazilian grants from CNPq [#309633/2021-4, #307852/2019-9, #307689/2022-0, #405027/2021-4, and #427946/2018-2], Coordination for the Improvement of Higher Education Personnel [CAPES, Brazil, finance code 001] as well as a grant from SETI/Araucária Foundation, MCTI/CNPq, and Paraná State Government under the PRONEX call [agreement 014/2017, protocol 46.843].