Identification of PPARγ agonists from natural sources

The peroxisome proliferator-activated receptors (PPARs) have been in focus for more than a decade for the development of drugs to treat and/or prevent diseases associated with the metabolic syndrome (MS). The PPARs (α, δ, γ) are nuclear receptors (NRs) highly involved in lipid and energy metabolism and hence, targets for treating MS-related disorders. In particular PPARγ that is a key regulator of insulin sensitivity is the target of many conventional drugs, although this may result in severe side effects. However, such side effects could be avoided using selective modulators or partial agonists instead [1,2]. Natural products have proven to be a valuable source of PPAR activators [3] of which some have demonstrated interesting partial agonist activities in vivo [4]. In our studies on identification of PPAR modulators from natural sources we use different approaches such as bioassay-guided fractionations, structure-activity relationships, and pharmacophore-modeling [5,6,7,8]. This has led to the identification of new potential PPARγ agonists from purple coneflower (Echinacea purpurea) (L.) Moench [5], a plant not traditionally used to treat MS. For traditional anti-diabetic remedies such as sage (Salvia officinalis L.) and elderflowers (Sambucus nigra L.) PPAR activating properties have been identified suggesting a mechanism of action involving these NRs [6,7]. This was also the case when a pharmacophore-driven approach led to the identification of novel PPARγ partial agonists from mastic gum (Pistacia lentiscus L.). Hence, there is a large potential for finding modulators of these versatile NRs amongst natural products and hence important information about their mechanisms of action and their use as drug candidates.

Keywords: Metabolic syndrome, PPAR, natural products, medicinal plants, bioassay-guided fractionation

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