2,4 Dinitrophenol as Medicine

Abstract

In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950’s to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin® and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescription, as both a sleeping pill and “morning sickness” anti-nausea medication targeting pregnant women in the 1950’s. The “thalidomide babies” became the case-in-point for the need of strict guidelines by the U.S. Food & Drug Administration (FDA) or full multi-species teratogenicity testing before drug approval. More recently it was found that thalidomide is useful in graft versus host disease, leprosy and resistant tuberculosis treatment, and as an anti-angiogenesis agent as a breakthrough drug for multiple myeloma (except for pregnant female patients). Decades of diabetes drug discovery research has historically focused on every possible angle, except, the energy-out side of the equation, namely, raising mitochondrial energy expenditure with chemical uncouplers. The idea of “social responsibility” allowed energy-in agents to be explored and the portfolio is robust with medicines of insulin sensitizers, insulin analogues, secretagogues, SGLT2 inhibitors, etc., but not energy-out medicines. The primary reason? It appeared unorthodox, to return to exploring a drug platform used in the 1930s in over 100,000 obese patients used for weight loss. This is over 80-years ago and prior to Dr Peter Mitchell explaining the mechanism of how mitochondrial uncouplers, like 2,4-dinitrophenol (DNP) even worked by three decades later in 1961. Although there is a clear application for metabolic disease, it was not until recently that this platform was explored for its merit at very low, weight-neutral doses, for treating insidious human illnesses and completely unrelated to weight reduction. It is known that mitochondrial uncouplers specifically target the entire organelle’s physiology non-genomically. It has been known for years that many neuromuscular and neurodegenerative diseases are associated with overt production of reactive oxygen species (ROSs), a rise in isoprostanes (biomarker of mitochondrial ROSs in urine or blood) and poor calcium (Ca2+) handing. It has also been known that mitochondrial uncouplers lower ROS production and Ca2+ overload. There is evidence that elevation of isoprostanes precedes disease onset, in Alzheimer’s Disease (AD). It is also curious, why so many neurodegenerative diseases of known and unknown etiology start at mid-life or later, such as Multiple Sclerosis (MS), Huntington Disease (HD), AD, Parkinson Disease, and Amyotrophic Lateral Sclerosis (ALS). Is there a relationship to a buildup of mutations that are sequestered over time due to ROSs exceeding the rate of repair? If ROS production were managed, could disease onset due to aging be delayed or prevented? Is it possible that most, if not all neurodegenerative diseases are manifested through mitochondrial dysfunction? Although DNP, a historic mitochondrial uncoupler, was used in the 1930s at high doses for obesity in well over 100,000 humans, and so far, it has never been an FDA-approved drug. This review will focus on the application of using DNP, but now, repositioned as a potential disease-modifying drug for a legion of insidious diseases at much lower and paradoxically, weight neutral doses. DNP will be addressed as a treatment for “metabesity”, an emerging term related to the global comorbidities associated with the over-nutritional phenotype; obesity, diabetes, nonalcoholic steatohepatitis (NASH), metabolic syndrome, cardiovascular disease, but including neurodegenerative disorders and accelerated aging. Some unexpected drug findings will be discussed, such as DNP’s induction of neurotrophic growth factors involved in neuronal heath, learning and cognition. For the first time in 80’s years, the FDA has granted (to Mitochon Pharmaceutical, Inc., Blue Bell, PA, USA) an open Investigational New Drug (IND) approval to begin rigorous clinical testing of DNP for safety and tolerability, including for the first ever, pharmacokinetic profiling in humans. Successful completion of Phase I clinical trial will open the door to explore the merits of DNP as a possible treatment of people with many truly unmet medical needs, including those suffering from HD, MS, PD, AD, ALS, Duchenne Muscular Dystrophy (DMD), and Traumatic Brain Injury (TBI).

Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity

“…Despite its success in reducing body weight (up to 3 lbs per week) in high doses, DNP caused substantial side effects, including rashes, cataracts, and even death due to hyperthermia (160). Nevertheless, DNP was used as an off-label weight-loss medication in the 1930s (160) and has the distinction of being one of the first drugs banned by the FDA (161). Besides direct uncoupling of oxidative phosphorylation, DNP increases intracellular cAMP, likely through the activation of adenylyl cyclase and/or inhibition of phosphodiesterase activity (160).…”

“…Nevertheless, DNP was used as an off-label weight-loss medication in the 1930s (160) and has the distinction of being one of the first drugs banned by the FDA (161). Besides direct uncoupling of oxidative phosphorylation, DNP increases intracellular cAMP, likely through the activation of adenylyl cyclase and/or inhibition of phosphodiesterase activity (160). Elevated cAMP could then activate PKA and then downstream lipolysis and thermogenesis.…”

Fluorescein Derivatives as Antibacterial Agents Acting via Membrane Depolarization

“…The main arguments in favor of Mitchell's chemiosmotic theory were based on the ability of uncouplers to cause the collapse of the membrane potential by carrying protons across membranes. At present, there is a revival of interest in uncouplers because of the growing evidence of their broad-spectrum therapeutic efficacy [1][2][3][4][5][6][7][8][9], including antibacterial potency [10][11][12][13][14][15][16][17][18][19], which was actually found very early [20]. To this end, a series of esters of fluorescein were obtained and studied at our laboratory, manifesting themselves as rather effective mitochondrial uncouplers [21][22][23].…”

Ibrutinib suppresses intracellular mycobacterium tuberculosis growth by inducing macrophage autophagy

“…[6][7][8] Consequently, HDT drug candidates targeting the functions of macrophage, especially those involved in effective control of intracellular Mtb growth such as ROS production and autophagy, have showed promising effect against both drug-sensitive and drug-resistance Mtb infection. [9][10][11] Autophagy is critical for effective control of intracellular pathogens and mainly regulated by mTOR pathway, 12 and perturbations in the autophagy network have previously been associated with Mtb virulence 13 Accordingly, several molecules that with potential to enhance autophagy has been proposed as HDT candidate against TB. 4 , 11 The kinase PKC β lying downstream of BTK signaling has been reported as an essential regulator of AKT/mTOR signaling, 14 previous report has shown that inhibition of BTK by ibrutinib, which has been approved as firstline drug to treat chronic lymphocytic leukemia (CLL), significantly enhanced autophagy in cancer cell line glioblastoma through suppression of Akt/mTOR pathway.…”