Proposed Projects - DOCTORATES 4 COVID-19 FCT and AICIB Call
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1.Blunting the spike: Rationally designed inhibitors targeting the SARS-CoV-2 fusion protein
1. Blunting the spike: Rationally designed inhibitors targeting the SARS-CoV-2 fusion protein
Lab: Protein Modelling and Structural Genomics
Supervisor: Diana Lousa (ITQB NOVA)
Co-Supervisors: João Vicente and Cláudio M. Soares (ITQB NOVA)
Type of fellowship: National Fellowship
Brief description:
One of the most promising therapeutic targets of coronavirus is the spike (S) protein, which is crucial for viral entry, as it promotes fusion between the viral and host membranes, enabling the virus to insert its genetic material into the host cell and replicate. Although 3D structures of the S protein of different Coronaviruses are available, the full potential of this protein as a therapeutic target remains to be explored.
This project aims to fill this gap by using a combination of in-silico and experimental methods to rationally design, produce and test chemical and biological inhibitors targeting the S protein. Computational tools will be used to provide novel insights into the mechanisms of action of the S protein and design chimeric proteins (based on existing structural data) and small molecules that can bind and inactivate this protein. The designed proteins will be expressed and purified according to existing protocols for the ‘scaffold’ proteins, and their properties will be assessed by biophysical methods. The ability of the designed proteins and small molecules to interact with the S protein will be tested using biophysical assays such as surface plasmon resonance and isothermal titration calorimetry. Structural data obtained for the complexes formed between the S protein and the herein designed chimeric proteins will allow evaluating and improving the interaction through an iterative process. The evaluation of antiviral activity of the inhibitors will be done by collaborators, who will perform in vitro infection assays of human cells.
Other information: Candidates should have a Master degree in Biology, Chemistry, Biochemistry, Computational Biology or related areas and a strong motivation to conduct research in the proposed topic, using both computational and experimental techniques.
2. Sticking it to COVID-19: Tuning ACE2 and SARS-CoV/MERS-CoV antibodies to bind and neutralize SARS-CoV-2
Lab: Multiscale Modeling
Supervisor: Manuel N. Melo (ITQB NOVA)
Co-Supervisors: Miguel Castanho (iMM) and Isabel Abreu (ITQB NOVA)
Type of fellowship: National Fellowship
Brief description:
The ongoing COVID-19 outbreak calls for urgent development of therapeutic solutions. One strategy is to employ antibodies known to neutralize SARS-CoV-2 (SCV2) as therapies. However, COVID-19 is too recent for such antibodies to have been identified. On the other hand, following the past SARS and MERS coronavirus outbreaks, several anti-SARS-CoV (SCV) and anti-MERS-CoV (MCV) neutralizing antibodies have been characterized. These cannot, however, neutralize SCV2. This project’s strategy is to upgrade those antibodies to target SCV2 instead, leveraging the structural and functional similarities between SCV/MCV and SCV2. Additionally, the protein ACE2 — SCV2’s very target on host cell membranes — will itself be tuned to act as an antibody-like particle.
The approach will be based on the structural characterization that is available for ACE2 and at least four anti-SCV/anti-MCV antibodies. These five template proteins all bind the viral spike glycoprotein, blocking epitopes involved either in host cell recognition or in triggering envelope/membrane fusion. Computational methods will be used to design modified paratopes on the templates to enhance their binding to homologous epitopes on the SCV2 spike protein. At the ITQB-NOVA a large-scale computational screening of modifications will yield multiple optimized lead sequences and recombinant antibodies will be expressed from those leads. Antibody activity will then be characterized at the Institute of Molecular Medicine both biophysically and in an in vitro infection model.
This is a multidisciplinary project that will cover the design, production and testing of new antibody or antibody-like particles, with the applied goal of establishing new COVID-19 therapies.
