Non-antimicrobial tetracycline derivatives for Influenza
Johan Auwerx – firstname.lastname@example.org
Influenza is a respiratory disease caused in humans by Influenza virus A and B infections. Seasonal influenza occurring mainly in the winter season have been reported by WHO to infect each year over 1 billion individuals, with 3-5 million of severe cases and 300,000–500,000 influenza-related deaths yearly. Because of its high mutation rate, developing efficient drugs and vaccines is challenging. Thus, seasonal influenza vaccine effectiveness mostly depends on the forecasting accuracy of changes in the influenza genome. The severity of this disease, especially on high-risk patients with pre-existing respiratory pathology or immunodeficiency, creates an urgent need to develop new effective therapeutic strategies.
Influenza is characterized by upper respiratory tract infection symptoms such as fever, cough, and runny nose which commonly recover after 5-10 days. However, some cases of influenza virus infection are associated with more severe and persistent symptoms, due to an excessive inflammation response with organ damages and/or a secondary bacterial infection. The inflammatory response triggered after viral infection is fundamental to stop the proliferation of the pathogen. However, in the case of complicated influenza, the excessive and uncontrolled inflammatory response to the pathogen, instead of slowing down the progression of the infection, increases the susceptibility of the host to secondary infections and is associated with lung damage in the context of cytokine storm. As a result, an increasing number of anti-inflammatory drugs – often affecting the mitochondria, the seat of our anti-inflammatory response - are currently being investigated as potential treatments for influenza complications.
Among the currently available anti-inflammatory treatments, antibiotics such as tetracyclines derivatives have emerged as interesting potential drugs because of their antiviral properties. However, the widespread use of antibiotics in medicine has led to the emergence of antibiotic-resistant pathogens. Therefore, this course will be focused on the discovery of non-antimicrobial tetracycline derivatives. We will discuss and study the current knowledge on the inflammatory response to influenza and the role of mitochondrial stress signaling in this phenomenon. Based on this knowledge, the goal of your project will be to design a strategy to: (1) use inhibitors of inflammatory pathways to treat Influenza, and (2) identify new compounds/drugs that improve Influenza by targeting mediators of these inflammatory response. You will hence design a strategy to screen for inflammatory mediators and plan the preclinical development of such a drug to treat influenza infections. You will work in close collaboration with scientists that are engaged in a similar project in “real” life. The following items will have to be addressed in your research project:
1. Defining a product profile: Define the targeted disease and expected treatment outcome.
2. Target ID: What is the best target, mediators in inflammatory responses? What kind of inhibition do you want to achieve? Provide background and rational why you have chosen this target.
3. Target validation: How to make sure acting on the target will have the expected outcome without causing side effects?
- cell based studies
- animal models
- human genetics
- gene networks
4. Screening: How to design and execute a cost effective and instructive screen which will provide hits?
- compound libraries: natural, semi-synthetic, NCEs
- virtual screening
- high throughput/low content vs low throughput/high content,
- biochemical vs cell-based screen
- hit ID
5. Hit to Lead:
- understanding lead quality
- selectivity (off target effects)
- alerting structures (toxicophores)
- synthetic accessibility
- SAR using in vitro assays
6. Lead optimization: Getting all the desired properties in 1 compound = DC
- in vitro biochemical and cellular assays
- understanding properties (potency, selectivity, toxicology)
- pharmacokinetics, pharmacodymamics
7. Preclinical proof of concept (PCC):
- cell based assays
- animal models (preclinical POC)
General and Practical information
(A) Work will be planned, discussed, and evaluated during office hours. If not during regular course time, you should make an appointment by e-mail at <email@example.com>
(B) The scientists that will help you are Amelia, Alessia and Xiaoxu. Their e-mails are:
(C) You will be evaluated on: (1) participation in discussions during the group sessions; (2) group report (<25 A4 pages in MS Word); (3) group presentation (20 minutes – max 25 slides in MS ppt); and (4) an individual exam on your project and the general subject of translational research. The exam is scheduled for December 2020. The exact date will be communicated in due course.
(D) Plagiarism will not be tolerated. Any infringement to the rules will cause the disqualification of the report with an “NA” as a score for the whole group. All statements in your report/presentation will have to be properly referenced.
(E) Background reading. The following papers/books are considered background and should be read before the first session of office hours, when we will test your knowledge about them. Some of these papers can be found on Moodle.
Griffin MO, Ceballos G, Villarreal FJ. Tetracycline compounds with non-antimicrobial organ protective properties: possible mechanisms of action. Pharmacol Res. 2011;63(2):102-107.
Krammer F, Smith GJD, Fouchier RAM, et al. Influenza. Nat Rev Dis Primers. 2018;4(1):3. Published 2018 Jun 28.
Tavares LP, Teixeira MM, Garcia CC. The inflammatory response triggered by Influenza virus: a two edged sword. Inflamm Res. 2017;66(4):283-302.
Williams EG, Auwerx J. The Convergence of Systems and Reductionist Approaches in Complex Trait Analysis. Cell. 2015;162(1):23-32.
West AP, Shadel GS. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol. 2017;17(6):363-375.
West AP, Khoury-Hanold W, Staron M, et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015;520(7548):553-557.
Houtkooper RH, Mouchiroud L, Ryu D, et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature. 2013;497(7450):451-457.
Moullan N, Mouchiroud L, Wang X, et al. Tetracyclines Disturb Mitochondrial Function across Eukaryotic Models: A Call for Caution in Biomedical Research. Cell Rep. 2015;10(10):1681-1691.
Pellegrino MW, Nargund AM, Kirienko NV, Gillis R, Fiorese CJ, Haynes CM. Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature. 2014;516(7531):414-417.
Liu Y, Samuel BS, Breen PC, Ruvkun G. Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature. 2014;508(7496):406-410.
Mottis A, Herzig S, Auwerx J. Mitocellular communication: Shaping health and disease. Science. 2019;366(6467):827-832.
Quirós PM, Mottis A, Auwerx J. Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol. 2016;17(4):213-226.