Efficacy | EPFL Graph Search

Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as effectiveness, and it has often been used synonymously, although in pharmacology a distinction is now often made between efficacy and effectiveness. The word efficacy is used in pharmacology and medicine to refer both to the maximum response achievable from a pharmaceutical drug in research settings, and to the capacity for sufficient therapeutic effect or beneficial change in clinical settings. Pharmacology Intrinsic activity In pharmacology, efficacy (Emax) is the maximum response achievable from an applied or dosed agent, for instance, a small molecule drug. Intrinsic activity is a relative term for a drug's efficacy relative to a drug with the highest observed efficacy. It is a purely descriptive term that has little or no mechanistic interpretation. In order for a drug to have an effect, it needs to bind to its target, and

Towards Elucidating the Mechanism of Action of Biguanides

Nicolas Peter Goeldel

Diabetes type 2 patients are insensitive to insulin, a condition that leads to reduced glucose uptake by cells and, subsequently, to high concentration of glucose in the blood. For 60 years, biguanides have been one of the few effective therapeutics in reducing blood glucose levels. These include phenformin and metformin, the latter the most frequently prescribed drug for type 2 diabetes up to date. Although the mechanism of action of biguanides remains imperfectly understood the efficacy of metformin in the treatment of type 2 diabetes is unchallenged. Metformin was developed based on the natural product galegine. Initially, metformin was believed to interfere with complex 1 of the respiratory chain leading to a reduced ratio of [ATP]/[ADP.AMP] activating the enzyme AMP-activated protein kinase (AMPK). The assumption that the effects of metformin are exclusively mediated by AMPK has recently been challenged by genetic loss-of-function experiments. Since then it has been hypothesized that metformin inhibits hepatic gluconeogenesis by interfering with the cAMP/PKA pathway acting as a glucagon antagonist. Another study has suggested that biguanides lead to an altered hepatocellular redox state through inhibition of mitochondrial glycerophosphate dehydrogenase (mGPD) yielding a decreased liver glucose output. However, none of the studies show a direct binding of biguanides to the assumed protein effector. In this thesis, we provide for the first time ever evidence for biguanides binding directly a cytosolic protein, Coronin1C. This study provides evidence that biguanides may indeed antagonize the action of glucagon, thus reducing fasting glucose levels, through modulation of Coronin1C. Coronin1C is a key regulator of actin homeostasis but is also involved directly in relaying extracellular signals through the cAMP/PKA pathway. It has been shown that functional modulation of Coronin1C through biguanide binding i) alters actin homeostasis, ii) attenuates cAMP/PKA pathway signaling and iii) leads to a displacement of AMPK from Coronin1C. Modulation of Coroninâs function is a new and potentially crucial piece of the puzzle as to how biguanides exert their therapeutic efficacy. A Coronin1C centered mechanism of action of biguanides is intriguing as it coherently links previously described cellular effects that cannot be explained with the currently available theories. This study sheds also light on biguanides anti-cancer properties. A better understanding of biguanides mechanism of action could lead to improved outcomes for millions of diabetics worldwide as well as it could provide a new protein target for the treatment of cancer.

EPFL2018

Redox-responsive interleukin-2 nanogel specifically and safely promotes the proliferation and memory precursor differentiation of tumor-reactive T-cells

Hacer Arik, Li Tang, Lixia Wei, Yuqing Xie

Interleukin-2 (IL-2) is a potent T-cell mitogen that can adjuvant anti-cancer adoptive T-cell transfer (ACT) immunotherapy by promoting T-cell engraftment. However, the clinical applications of IL-2 in combination with ACT are greatly hindered by the severe adverse effects such as vascular leak syndrome (VLS). Here, we developed a synthetic delivery strategy for IL-2 via backpacking redox-responsive IL-2/Fc nanogels (NGs) to the plasma membrane of adoptively transferred T-cells. The NGs prepared by traceless chemical cross-linking of cytokine proteins selectively released the cargos in response to T-cell receptor activation upon antigen recognition in tumors. We found that IL-2/Fc delivered by T-cell surface-bound NGs expanded transferred tumor-reactive T-cells 80-fold more than the free IL-2/Fc of an equivalent dose administered systemically and showed no effects on tumor-infiltrating regulatory T-cell expansion. Intriguingly, IL-2/Fc NG backpacks that facilitated a sustained and slow release of IL-2/Fc also promoted the CD8(+) memory precursor differentiation and induced less T-cell exhaustion in vitro compared to free IL-2/Fc. The controlled responsive delivery of IL-2/Fc enabled the safe administration of repeated doses of the stimulant cytokine with no overt toxicity and improved efficacy against melanoma metastases in a mice model.

2019

Innovative Tools and in vivo Methods for Tuberculosis Drug Discovery and Development

Raphael Christopher Sommer

Worldwide, tuberculosis (TB) is the leading cause of death due to a single infectious agent, claiming 1.6 million human lives and causing >10 million new cases in 2017 alone, mostly in low-income regions. The intracellular pathogen Mycobacterium tuberculosis is the etiological agent and generally infects the lungs. Although treatments exist, curing TB requires long and often expensive chemotherapy, frequently accompanied by undesirable side-effects. In the absence of an effective vaccine and with the increasing emergence of multidrug resistance, new and more powerful antibiotics are urgently needed to control the global TB crisis. In this respect, benzothiazinones (BTZs), a class of new anti-TB compounds, have recently been discovered. Macozinone (PBTZ169), that has reached phase I and II clinical trials in Switzerland and Russia, respectively, is undoubtedly the most promising drug of this category. We derivatized PBTZ169 into a fluorescent chemical probe that efficiently, covalently and selectively labels the enzyme DprE1, thereby localizing the target of BTZs to the periplasm at the poles of actinobacteria. We further discuss the potential applications of such probes for in vivo imaging, mycobacterial detection and designing new diagnostic tools. In general, the search for novel anti-mycobacterial drugs is an extremely long process, delaying the progression of new compounds down the pipeline and to the clinic. Assessing drug efficacy in vivo typically requires extensive resources and is time-consuming. This process can be shortened by applying alternative and innovative methods devised in this thesis, namely the implementation of in vivo imaging procedures and use of the zebrafish embryo model of mycobacterial infection for drug discovery and development. In vivo imaging enables bacterial loads in animal models to be assessed in real time, by means of fluorescence or bioluminescence imaging. We constructed, optimized and characterized genetically engineered near-infrared fluorescent reporters of the pathogens Mycobacterium marinum and M. tuberculosis that allow direct visualization of bacteria in infected zebrafish and mice, respectively. Furthermore, we show that the fluorescence level accurately reflects the bacterial load, as determined by colony forming unit enumeration, thus enabling the efficacy of antibiotic treatment to be assessed in live animals. Alternatively, we applied autobioluminescent M. tuberculosis to evaluate drug efficacy in mice and demonstrated that our system enables the therapeutic response to be followed in real time. Longitudinal imaging also reduces the number animals required thus providing a substantial gain of time and resources. Finally, the zebrafish embryo is an inexpensive and faster alternative model that has been applied to investigate mycobacterial pathogenesis. We implemented this model of M. marinum infection and successfully applied it to assess the activity of several drugs in vivo. Altogether, the innovative methods described in this work are advantageous for TB drug discovery and development, especially for the in vivo evaluation of new anti-mycobacterial candidates, and provide more ethically acceptable approaches and biomedical applications.

EPFL2019