Adaptive Membrane Fluidity Modulation: A Feedback Regulated Homeostatic System Hiding in Plain Sight

Abstract

The structure of the plasma membrane affects its function. Changes in membrane fluidity with concomitant effects on membrane protein activities and cellular communication often accompany the transition from a healthy to a diseased state. Although deliberate modulation of membrane fluidity with drugs has not been exploited to date, the latest data suggest the "druggability" of the membrane. Azelaic acid esters (azelates) modulate plasma membrane fluidity and exhibit a broad range of immunomodulatory effects in vitro and in vivo. Azelates represent a new class of drugs, membrane active immunomodulators (MAIMs), which use the entire plasma membrane as the target, altering the dynamics of an innate feedback regulated homeostatic system, adaptive membrane fluidity modulation (AMFM). A review of the literature data spanning >200 years supports the notion that molecules in the MAIMs category including known drugs do exert immunomodulatory effects that have been either neglected or dismissed as off-target effects.A literature search was conducted using PUBMED, MEDLINE, and Library of Congress databases to capture peer-reviewed research articles (including reviews and metaanalyses), published through August 27, 2021, with the earliest record dating from 1801. The search terms included "plasma membrane" AND "fluidity" OR "plasticity" OR "rigidity". Secondary searches combined keywords consisting of individual chemical entities listed in this manuscript (for example, cholesterol, ethanol, turpentine) and physiological conditions (for example pain, fever, disease). The collected abstracts and/or full papers were surveyed by both authors in order to confirm article relevancy to the topic.

Membrane Active Immunomodulator As a Novel Therapy for an Infectious Bacterial Disease, Buruli Ulcer

“…We have identified a novel family of immunomodulatory compounds that change the plasma membrane fluidity of host cells and consequently alter the activities of membrane-associated proteins, receptors and microbial toxins that interact with the plasma membrane. Esters of azelaic acid (azelates) are the first recognized agents of a new class of drugs that we have named membrane-active immunomodulators (33)(34)(35). The azelates counteracted detrimental effects of multiple pathogen-associated molecular pattern (PAMP) receptor agonists including LPS in cultured human cells and in vivo.…”

Azelaic Acid Esters as Pluripotent Immunomodulatory Molecules: Nutritional Supplements or Drugs

“…We have noted in the past that the levels of AZA and its esters appear to be dynamically regulated immune responses, as illustrated by their increase in the response to toxin exposure [7].…”

“…AZA modulates the innate immune responses in human skin [4,5]. The immunomodulatory role of the azelates, and especially diethyl azelate (DEA), has been discovered only recently [6,7]. These findings suggest highly conserved functions of AZA and azelates in multicellular organisms.…”

“…However, the azelates have been little explored as drugs. We have identified the azelates as representatives of a new class of drugs and discovered a number of potential applications of DEA and other azelates in treating diverse human pathologies [6,7,21].…”

Diethyl Azelate for the Treatment of Brown Recluse Spider Bite, a Neglected Orphan Indication

“…We have identified a novel class of drugs that we refer to as Membrane Active Immunomodulators (MAIMs) that use the entire cell plasma membrane as their target (15,16). MAIMs alter membrane fluidity and shift the innate feedback mechanism regulating fluidity homeostasis mechanism, which we have named adaptive membrane fluidity modulation (AMFM).…”