CoV2-ACE2
Implementation of a research platform for thescreening of molecules interfering with the specific binding between the Spikeprotein of th SARS-CoV-2 virus and human angiotensin converting enzyme ACE2
Abstract
Thesudden viral pandemic caused by the Betacoronavirus SARS-CoV-2 triggers a quickresponse of the world scientific and medical community. It was then quicklyshown that the new virus SARS-CoV-2 was strongly related to the SARS-CoV-1virus that emerged in 2003 and that the two viruses possesses several commonfeatures. One of them is the entry mechanism in human cells (nasal and lungcells); this latter rests on the specific and strong interaction between theprotein S (Spike) located at the surface of the viral particle and the humantransmembrane protein ACE2 (Angiotensin converting enzyme 2). The affinitybetween the two proteins is higher with the Spike protein of SARS-CoV-2relative to those of SARS-CoV-1 suggesting that the new pandemic threat is theresult of an evolution process, possibly mediated by genetic recombination. Theexperimental characterization of this interaction could be made using SPR(Surface Plasmon Resonance) methods and the use of this methodology shouldpermit us to identify valuable molecules and ligands able to interfere withthis interaction. Such molecules could be then developed and tuned to obtaintherapeutic agents.
Screening molecules interfering with the specific binding of SARS-CoV-2 virus
SARS-CoV-2 is the viral agent related to the present world pandemic and is the third coronavirus to cross the inter-speciesbarrier since the beginning of the 21th century and to cause lethal and verycontagious pneumonia.
The past research on the first viral agent, SARS-CoV-1,leads to the identification of several key elements related to the infectionprocess of human cells, and namely the role of the human transmembrane protein ACE2 (Angiotensin Converting Enzyme 2) present in the lung, cardiac and nasalcells and that appear to constitute the main target of the virus.
Recent researches on SARS-CoV-2 have permitted to confirm the major involvement of ACE2in the mechanism of the entry of the virus in human cells. The viral partner ofthis process is the Spike protein S that is located at the surface of the viralparticle giving to the virus an aspect of solar corona. It was also shownthat the main domain of interaction of Spike protein with ACE2 is the Receptor-Binding-Domain (RBD), and this latter exhibit significative differences between the twoviruses (SARS-CoV-1 and SARS-CoV-2); this suggests an evolutive processprobably mediated by genetic recombination events.
The detailed study of theaffinities between the RBD domain of the S protein and human ACE2 is crucial toobtain a best understanding of the role of the different amino-acids present atthe interface between the two proteins in the association process.
These analyses could also constitute an efficient method to identify ligands andmolecules able to interfere in this process. Quantitative analysis of theinteractions needs the use of powerful SPR (Surface Plasmon Resonance) methodsthat are among the unique methods that allow the correct measurements of thevery high affinities involved in these interaction processes.
Severalstrategies of researches will be employed, they will be based on previous waysof research initiated in the fight against SARS-CoV-2.
- The first one will use peptideligands and constitutes a promising approach already experimented in the frameof S protein-ACE2 interaction.
- The second is based on the use of organicmolecules of the emodin family (anthraquinone) that will be obtained bychemical syntheses performed in the team of Prof.J.Xie, the substitutions andmodifications of these ligands will be designed and guided by molecularmodelling methods that we mastered in our team at IDA-LBPA.
Contacts
LBPA
- Olivier MAUFFRET
- Claude NOGUES
- Brahim HEDDI,
- Loussiné ZARGARIAN
- Marco PASI
PPSM
- Joanne XIE
- Stéphane MAISONNEUVE