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Ph.D. (M/F) in structural bioinformatics

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General information

Reference : UMR9198-FABLEC-004
Workplace : ORSAY
Date of publication : Tuesday, June 16, 2020
Scientific Responsible name : Fabrice Leclerc, Yann Ponty
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 November 2020
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly

Description of the thesis topic

In silico design of modified oligonucleotides and bioconjugates against protein targets in Alzheimer's disease

New therapeutic strategies have emerged using aptamers that are high-affinity
ligands generated using a procedure called SELEX. Many aptamers are currently
tested at different stages of clinical trials [1]. Some aptamers
have been generated against different therapeutic targets of AD: BACE1, Aβ
oligomers, etc [2]. However, their use as drugs remains limited due
to their lack of selectivity because they can bind to a myriad of alternative
cellular targets. As a result, off-target effects are frequently observed as in
all RNA-based therapeutic strategies using oligonucleotides as gene silencers
(siRNA, shRNA, CRISPR/gRNA, etc). To increase their specificity and selectivity,
a class of chemically-modified aptamers has been designed by SELEX. Such
modified aptamers (SOMAmer) have been recently selected in vitro to
bind IL-1α and inhibit its signaling pathway [3]. Nevertheless,
various limitations remain due to technical constraints in SELEX. Here, we
propose a strategy to design in silico modified aptamers or
pseudo-aptamers that will overcome these limitations.

BACE1 and several APP-derived fragments other than Aβ considered as toxic (βAPP
C99 [4]) are drug targets of interest. Other potential protein targets such as
metalloproteinases (MMP) have also been studied at IPMC [5]. BACE1 is the
first model system which is currently studied to provide the proof of concept of
this innovative strategy to design a new class of ligands and biosensors for the
diagnosis and therapies of AD. An aptamer effectively inhibits BACE1 in a cell
model [6]. Our general goal is to design pseudo-aptamers that
will match or outrank aptamers generated by SELEX or other ligands (antibody,
drug, etc.) in terms of binding affinity and specificity with limited or
neglecting off-target effects.

A fragment-based approach [7-9] will be used to design ligands against the
different selected protein targets of AD. In a first stage, the Ph.D. student
will provide a first contribution to the study on BACE1 on three aspects: (1)
the design of ligands targeting the allosteric binding site (exosite) of BACE1
[10], (2) the design of nucleotidic bioconjugates (porting the method for
reconstruction of ligands from fragments), (3) the development and
implementation of a workflow for the prediction of relative affinities of
designed ligands. On the other hand, he will also develop a novel method for the
fragment-based reconstruction of ligands. The method will rely on a graph
modeling of the fragment connectivity, enabling the implementation of an
efficient combinatorial algorithm, interactively informed by a local refinement
of consecutive fragments. This hybrid combinatorial/3D approach should allow
overcoming limitations, identified by the state-of-the-art, related to the depth
of the conformational sampling step [11,12]. The proposed ligands can be
validated experimentally in vitro at RSSF or in vivo by our collaborator at IPMC
[4,5]. We will apply the best strategies to the other selected AD targets.

Bibliographic references

[1] J. Zhou and J. Rossi, “Aptamers as targeted therapeutics: current potential
and challenges.,” Nature Reviews Drug Discovery, vol. 16, pp. 181–202, Mar.
2017.
[2] J. Qu, S. Yu, Y. Zheng, Y. Zheng, H. Yang, and J. Zhang, “Aptamer and
its applications in neuro- degenerative diseases.,” Cellular and molecular life
sciences : CMLS, vol. 74, pp. 683–695, Feb. 2017.
[3] X. Ren, A. D. Gelinas, I.
von Carlowitz, N. Janjic, and A. M. Pyle, “Structural basis for IL-1𝛼 re-
cognition by a modified DNA aptamer that specifically inhibits IL-1𝛼
signaling.,” Nature Com- munications, vol. 8, p. 810, Oct. 2017.
[4] A.
Bourgeois, I. Lauritzen, T. Lorivel, C. Bauer, F. Checler, and R.
Pardossi-Piquard, “Intraneur- onal accumulation of C99 contributes to synaptic
alterations, apathy-like behavior, and spatial learning deficits in 3×TgAD and
2×TgAD mice.,” Neurobiology of aging, vol. 71, pp. 21–31, Nov. 2018.
[5] K.
Baranger, A. E. Bonnet, S. D. Girard, J.-M. Paumier, L. García-González, W.
Elmanaa, A. Bern- ard, E. Charrat, D. Stephan, C. Bauer, K. Moschke, S. F.
Lichtenthaler, F. S. Roman, F. Checler, M. Khrestchatisky, and S. Rivera,
“MT5-MMP Promotes Alzheimer's Pathogenesis in the Frontal Cortex of 5xFAD Mice
and APP Trafficking in vitro,” Frontiers in Molecular Neuros- cience, vol. 9, p.
517, Jan. 2017.
[6] H. Liang, Y. Shi, Z. Kou, Y. Peng, W. Chen, X. Li, S. Li, Y.
Wang, F. Wang, and X. Zhang, “Inhibition of BACE1 Activity by a DNA Aptamer in
an Alzheimer's Disease Cell Model.,” PLOS ONE, vol. 10, no. 10, pp. e0140733–14,
2015.
[7] F. Leclerc and M. Karplus, “MCSS-based predictions of RNA binding
sites,” Theoretical Chem- istry Accounts: Theory, Computation, and Modeling
(Theoretica Chimica Acta), vol. 101, pp. 131–137, Feb. 1999.
[8] N. Chevrollier
and F. Leclerc, “MCSS-based Docking and Improved Scoring of Protein- Nucleotide
Complexes: I. A step forward to the Fragment-Based Design of Oligonucleotides,”
bioRxiv, vol. 14, p. 500, May 2019.
[9] N. Chevrollier, Modélisation par docking
des interactions entre protéine et ARN simple-brin. PhD thesis, Ecole doctorale:
”Structure et Dynamique des Systèmes Vivants”, Université Paris Saclay, May
2019.
[10] W. Wang, Y. Liu, and R. A. Lazarus, “Allosteric inhibition of BACE1
by an exosite-binding anti- body.,” Current Opinion in Structural Biology, vol.
23, pp. 797–805, Dec. 2013.
[11] I. Chauvot de Beauchene, S. J. de Vries, and M.
Zacharias, “Fragment-based modelling of single stranded RNA bound to RNA
recognition motif containing proteins,” Nucleic Acids Research, vol. 44, pp.
4565–4580, 04 2016.
[12] I. Chauvot de Beauchene, S. J. de Vries, and M.
Zacharias, “Binding site identification and flex- ible docking of single
stranded rna to proteins using a fragment-based approach,” PLOS Com- putational
Biology, vol. 12, pp. 1–21, 01 2016.

Work Context

I2BC is a large institute affiliated to CNRS, CEA, and Université Paris Saclay
including five departments. The RSSF laboratory, belonging to the Genome Biology
Department, has extended expertise on RNAs (non-coding RNAs, structure, and
interactions of RNAs, function, etc.) through bioinformatics approaches. The
laboratory is affiliated to the doctoral school "Structure and Dynamics of
Living Systems" from the Unversité Paris Saclay. The lead scientist is a
permanent CNRS agent, specialized in the structure/function relationships of
RNAs. The co-supervisor acts as the head of the AMIBio team at the "Laboratoire
d'Informatique de l'École Polytechnique" (LIX), and possesses significant
expertise in combinatorial algorithms applied to RNA bioinformatics.

The institute offers computational resources, technical, and scientific support,
as well as a collaborative environment, especially for the development of codes
and software.

The thesis subject ties in with a multidisciplinary project (bioinformatics,
computer science, biology, chemistry) that includes a foreign laboratory of
computational chemistry (LQCT) and a french experimental laboratory
internationally recognized on AD (IPMC). The Ph.D. student will collaborate with
other members from RSSF, with the AMIBio team at LIX, and with our collaborators for the experimental validations.

Additional Information

Keywords: Structural bioinformatics, Structure-based Ligand Design (SBDD), Fragment-Based Ligand Design (FBLD), Combinatorial Algorithms, Molecular Modeling, Molecular Simulations, Quantitative Structure-Activity Relationships (QSAR)

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