The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins

Abstract

Statins are a class of drugs used to lower low-density lipoprotein cholesterol and are amongst the most prescribed medications worldwide. Most statins work as a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR), but statin intolerance from pleiotropic effects have been proposed to arise from non-specific binding due to poor enzyme-ligand sensitivity. Yet, research into the physicochemical properties of statins, and their interactions with off-target sites, has not progressed much over the past few decades. Here, we present a concise perspective on the role of statins in lowering serum cholesterol levels, and how their reported interactions with phospholipid membranes offer a crucial insight into the mechanism of some of the more commonly observed pleiotropic effects of statin administration. Lipophilicity, which governs hepatoselectivity, is directly related to the molecular structure of statins, which dictates interaction with and transport through membranes. The structure of statins is therefore a clinically important consideration in the treatment of hypercholesterolaemia. This review integrates the recent biophysical studies of statins with the literature on the physiological effects and provides new insights into the mechanistic cause of statin pleiotropy, and prospective means of understanding the cholesterol-independent effects of statins.

Periodontal and Peri-Implant Diseases and Systemically Administered Statins: A Systematic Review

“…In particular, systemic statins may be variously beneficial for periodontitis and peri-implantitis due to their main and pleiotropic effects. Indeed, combined with the hypolipidemic effects, statins have also shown anti-inflammatory and antioxidant activities, on the one side, and stimulating properties affecting endothelial function, angiogenesis and bone formation on the other side [46]. Noteworthy, in periodontal subjects, statins have been found able to reduce osteoclasts activity and bone resorption [39], to increase Interleukin-(IL-)10 in gingival crevicular fluid while decreasing IL-1B [42], together with IL-6 and IL-8 [31] and to inhibit the release of matrix metalloproteinase-(MMP-)1, MMP-2, MMP-3 and MMP-9 [25,47], finally lowering periodontal tissues inflammation and destruction.…”

A Novel Statin Compound from Monacolin J Produced Using CYP102A1-Catalyzed Regioselective C-Hydroxylation

“…The metabolism processes of the statins in the human body should be considered regarding their functions as they depend on the chemical structure of each statin [39]. Human P450s have an important role in the clinical drug metabolism of statin drugs [40,41].…”

Anti-flavivirus Properties of Lipid-Lowering Drugs

“…Interestingly only lipophilic STAs showed anti-ZIKV effects, suggesting that lipophilicity is a crucial antiviral property (Españo et al, 2019). In this regard, there is evidence that the lipophilicity of STAs is related to the specificity, efficacy, and pleiotropic effects of these drugs because it allows interaction with lipid membranes (Murphy et al, 2020). However, the role of structure and biophysical properties on the antiviral effects of STAs has been understudied, and there are not in vivo studies to confirm that the antiviral properties of these drugs are restricted to lipophilic STAs.…”