Paper - Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b

Type: Paper
Author: Trevor Marshall PhD, Robert E. Lee, Frances E. Marshall
Publication: Theoretical biology & medical modelling
Citation: Marshall, T.G., Lee, R.E. & Marshall, F.E. Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b. Theoretical biology & medical modelling 3, 1(2006).
See also: full text; PubMed Central record

And see Editor's note below



There have been indications that common Angiotensin Receptor Blockers (ARBs) may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1,25-dihydroxyvitamin-D. This receptor mediates the expression of regulators as ubiquitous as GnRH (Gonadatrophin hormone releasing hormone) and the Parathyroid Hormone (PTH). Additionally we examined Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma), which affects the function of phagocytic cells, and the C-CChemokine Receptor, type 2b, (CCR2b), which recruits monocytes to the site of inflammatory immune challenge.


Telmisartan was predicted to strongly antagonize (Ki≈0.04nmol) the VDR. The ARBs OlmesartanMedication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. Also known by the trade name Benicar. , Irbesartan and Valsartan (Ki≈10 nmol) are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki≈30 nmol) and Losartan (Ki≈70 nmol) may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki≈0.3 nmol), while Losartan (Ki≈3 nmol), Irbesartan (Ki≈6 nmol), Olmesartan and Valsartan (Ki≈12 nmol) also seem likely to have significant PPAR modulatory activity. Olmesartan and Irbesartan (Ki≈9 nmol) additionally act as antagonists of a theoretical modelof CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the AngiotensinII Type1 receptor (AT2R1) has been presented.


Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the activation of two key nuclear receptors-VDR and PPARgamma. If our simulations are confirmed by experiment, it is possible that ARBs may become useful as potent anti-inflammatory agents, in addition to their current indication as cardiovascular drugs.

Editor's note

(since 2008) Professor Marshall now says

I am certain that the primary mode of action of Olmesartan is agonism of the human VDR, and the subsequent reconditioning of the human immune system.

I was conservative in that paper, and didn't claim Benicar as an agonist, but that had changed by Karolinska (as I collected more data) and now the molecular dynamics has firmly confirmed its remarkable similarity to 1,25-D in the VDR binding pocket (same residues, same hydrogen bonding, etc). Out of the pocket it is different in conformation, but my knowledge of the VDR has progressed to the point where I understand that only the top of the binding pocket is important, not the 'tail'.

I am sure that olmesartan is active in some of the microbes. The early 1990's research on ARBs identified that fact. I am not sure what exactly the effect on the microbes is, if any. I don't think it is direct killing, as the difference we see between folks' reaction to Benicar are now being readily quantified in terms of their D metabolism (by both myself and Dr Greg Blaney).

Our early papers say Benicar is an antagonist because 99% of molecules antagonize, and less than 1% activate receptors. So you always start from that perspective (an antagonist unless proven otherwise). After about 6 months of exploring all the possibilities, you will note that my description changed around the middle of last year. Now that we have produced the Molecular Dynamics videos/data, definitely showing the actions of an agonist, probably a super-agonist, I now know exactly how Olmesartan, 125-D, and 25-D, function in the VDR.

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