给实验室的老师发一个招生广告，
在u.s. news世界大学排名榜单中，巴黎第十一大学，在2019年位列世界第30位。目前已合并为巴黎萨克雷大学，巴黎萨克雷大学在2020软科世界大学学术排名（arwu）排名全球第14名，欧陆第1名
prof. sandrine ongeri希望招收csc学生一位。
有兴趣的童鞋可以联系：prof. sandrine ongeri ：sandrine.ongeri@u-psud.fr

design and synthesis of fluorinated peptidomimetic foldamers

keywords
foldamers, peptidomimetics, fluorine, amyloid, neurodegenerative diseases, antimicrobial peptide, cell penetrating peptides biomembranes
profile and skills required
organic chemistry medicinal chemistry

project description
foldamers are defined as artificial folded molecular architectures able to mimic the structural properties of biomolecules.1 peptidomimetic foldamers have the potential to adopt stable secondary structure mimics that are not reached by natural small and flexible peptides and can dramatically increase the proteolytic stability. they are particularly promising in the frame of the increasing interest of peptide derivatives as “sweet spot” between small molecules and biopharmaceuticals.2 however, to our knowledge, only very scarce examples of fluorinated foldamers have been reported and no demonstration of any therapeutic interest has yet been shown.
the phd research project is part of a common project between two teams of biocis aiming to design, synthesize and test fluorinated peptidomimetic foldamers that have been unexplored to date in organic and in medicinal chemistry. the effect of the rational introduction of specific fluorinated amino acid scaffolds in foldamers will be evaluated on their ability to increase their biological activity and to stabilize well-defined secondary structure such as α-helices, β-strands and polyproline ii helices, thanks to the capacity of fluorine to greatly increase the local hydrophobicity and to strengthen hydrogen bonds. introduction of fluorinated amino acids should also increase their enzymatic and chemical stability.3 furthermore, fluorine “labeling” is a great advantage for 19f-nmr spectroscopy because of its 100% natural abundance and high sensitivity, in the absence of background signals.

the phd research project will focus on fluorinated peptidomimetic foldamers capable of mimicking beta or helical structures in order to interact with beta or helical structures of amyloid proteins. they will be also evaluated for their ability to interact with biomembranes in order to act as cell penetrating peptides (cpp) or antimicrobial peptides (amp), as it has been established that amyloid proteins, amp and cpp show similarities in their mechanism of interaction with biomembranes. the phd student will be invested in the design and synthesis of peptidomimetic molecules as well as in their structural study by molecular modeling and nmr.

field /domain /context of the project research
peptidomimetic/ foldamers / medicinal chemistry.
amyloid protein aggregation is involved in some 30 human diseases, including neurodegenerative diseases and type ii diabetes. these pathologies are incurable because no etiological treatment exists because of the lack of understanding of the phenomenon and the lack of early and selective diagnostic tools. the aggregation of amyloid proteins produces toxic oligomers and fibrillar deposits, causing dysfunction, damage of biomembranes and cell death. our strategy is to develop peptide mimics, inhibiting the presence of toxic oligomers of proteins involved in neurodegenerative diseases and type ii diabetes. our laboratory fluopepit/biocis has proved a strong experience in that field.5 we also have demonstrated more recently our interest in foldamers.6 cell penetrating peptides (cpp) and antimicrobial peptides (amp) interact with biomembranes. the collaborating team ecb/biocis has demonstrated his interest the field of cpp/amp and foldamers.7 both teams have a strong experience in fluorine chemistry.8

objective
our strategy is to develop peptide mimics adopting beta-hairpin and helix conformations, to inhibit the aggregation of amyloid proteins involved in neurodegenerative diseases and type ii diabetes. their ability to act as cpp/amp will be also evaluated.

methods
design and synthesis of peptidomimetics mimics of beta-hairpin or alpha-helix as ligand of soluble species of amyloid proteins. biophysicochemical evaluation (fluorescence spectroscopy, electrophoresis capillary, circular dichroism, ims-ms, transmission electron microscopy, nmr …). molecular modeling (conformational studies of the peptidomimetics).

expected results
understand the aggregation process involved in alzheimer's disease and type ii diabetes through molecular tools and prevent the presence of toxic species for neurons and pancreatic cells respectively. gain crucial information for guiding the rational design of fluorinated foldamers as amps and cpps.

supervision
sandrine ongeri and grégory chaume have a strong experience in supervising phd students. they are currently co-supervising one post-doctoral researcher. they will be responsible for the objectives and orientations of the research project as well as the follow-up scientific training and transversal skills, through meetings regular with the phd student and they will provide day-to-day coaching on the work of synthesis and biophysical evaluations. lab meetings are often organized within the two teams and biocis.

research program of the phd student
first year: design and synthesis of the first peptidomimetics mimics of beta-hairpin and helix.
second year: synthesis and conformational studies by nmr and molecular modeling of the peptidomimetics mimics of beta-hairpin and alpha-helix. evaluation of the prepared compounds by biophysicochemical evaluation (fluorescence spectroscopy, electrophoresis capillary, transmission electron microscopy, ims-ms).
third year: pharmacomodulations of the peptidomimetics in order to improve the activity and druggable properties. biophysicochemical and cellular evaluation.
fourth year: final pharmacomodulations of the peptidomimetics in order to improve the activity and druggable properties. biophysicochemical and cellular evaluation. 2-3 publications expected. oral and poster communications. around 6 months dedicated to the writing the phd manuscript and to the writing of publication.

the phd student will follow courses (around 80-100 hours in total) provided by the doctoral school, to improve and to broaden his scientific knowledge and to benefit from transferable skills (entrepreneurship, valorization, patenting, perspective of career…).
valorization/diffusion of the research results
poster and oral communications in international congress, high impact factor publications and potentially patents.
collaborations
- prof myriam taverna (galien, univ paris saclay) : capillary electrophoresis
- prof olivier lequin (umr7203, sorbonne université) and dr. carine van heijenoort (icsn, univ. paris saclay) : conformational analysis by nmr

references
1. s. h. gellman, acc. chem. res. 1998, 31, 173; b) g. guichard, y. huc, chem. commun. 2011, 47, 5933.
2. a) j. l. lau, m. k. dunn, bioorg. med. chem. 2018, 26, 2700; b) a. f. b. räder, m. weinmüller, f. reichart, a. schumacher‐klinger, s. merzbach, c. gilon, a. hoffman, h. kessler, angew. chem. int. ed. 2018, 57, 14414.
3. a) e. n. g. marsh, acc. chem. res. 2014, 47, 2878; b) a. a. berger, j.-s. völler, n. budisa, b. koksch, acc. chem. res. 2017, 50, 2093; c) g. a. clark, j. d. baleja, k. kumar, j. am. chem. soc. 2012, 134, 17912.
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6) a) n. tonali, i. correia, j. lesma, g. bernadat, s. ongeri, o. lequin, org. biomol. chem. 2020, 18, 3452. hot article collection. cover picture; b) j. kaffy, c. berardet, l. mathieu, b. legrand, m. taverna, f. halgand, g. van der rest, l. maillard, s. ongeri, chem. eur. j. 2020, doi.org/10.1002/chem.202001716. hot topic: amyloids wiley-vch.
7. a) grage, s. l.; kara, s.; bordessa, a.; doan, v.; rizzolo, f.; putzu, m.; kubař, t.; papini, a. m.; chaume, g.; brigaud, t.; afonin, s.; ulrich, a. s. chem. eur. j. 2018, 24, 4328; b) putzu, m.; kara, s.; afonin, s.; grage, s. l.; bordessa, a.; chaume, g.; brigaud, t.; ulrich, a. s.; kubař, t. biophys. j. 2017, 112, 2602.
8. a) m. mamone, e. morvan, t. milcent, s. ongeri and b. crousse, j. org. chem. 2015, 80, 1964; b) s. décamps, l. sevaille, s. ongeri, b. crousse, org. biomol. chem. 2014, 12, 6345; c) m. keita, j. kaffy, c. troufflard, e. morvan, b. crousse and s. ongeri. org. biomol. chem. 2014, 12, 4576; d) m. mamone, r. s. b. gonçalves, f. blanchard, g. bernadat, s. ongeri, t. milcent, b crousse, chemcomm 2017, 53, 5024; e) y. xu, i. correia, t. ha-duong, n. kihal, j-l soulier, j. kaffy, b. crousse, o. lequin, s. ongeri, beilstein j. org. chem. 2017, 13, 2842.
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[ last edited by chenhui0706 on 2020-12-27 at 22:35 ]

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