Powerful Avidity with a Limited Valency for Virus-Attachment Blockers on DC-SIGN: Combining Chelation and Statistical Rebinding with Structural Plasticity of the Receptor

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F23%3A00569104" target="_blank" >RIV/61388963:_____/23:00569104 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1021/acscentsci.2c01136" target="_blank" >https://doi.org/10.1021/acscentsci.2c01136</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acscentsci.2c01136" target="_blank" >10.1021/acscentsci.2c01136</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Powerful Avidity with a Limited Valency for Virus-Attachment Blockers on DC-SIGN: Combining Chelation and Statistical Rebinding with Structural Plasticity of the Receptor

Popis výsledku v původním jazyce

The C-type lectin receptor DC-SIGN has been highlighted as the coreceptor for the spike protein of the SARS-CoV-2 virus. A multivalent glycomimetic ligand, Polyman26, has been found to inhibit DC-SIGN-dependent trans-infection of SARS-CoV-2. The molecular details underlying avidity generation in such systems remain poorly characterized. In an effort to dissect the contribution of the known multivalent effects ─ chelation, clustering, and statistical rebinding ─ we studied a series of dendrimer constructs related to Polyman26 with a rod core rationally designed to engage simultaneously two binding sites of the tetrameric DC-SIGN. Binding properties of these compounds have been studied with a range of biophysical techniques, including recently developed surface plasmon resonance oriented-surface methodology. Using molecular modeling we addressed, for the first time, the impact of the carbohydrate recognition domains’ flexibility of the DC-SIGN tetramer on the compounds’ avidity. We were able to gain deeper insight into the role of different binding modes, which in combination produce a construct with a nanomolar affinity despite a limited valency. This multifaceted experimental–theoretical approach provides detailed understanding of multivalent ligand/multimeric protein interactions which can lead to future predictions. This work opens the way to the development of new virus attachment blockers adapted to different C-type lectin receptors of viruses.

Název v anglickém jazyce

Powerful Avidity with a Limited Valency for Virus-Attachment Blockers on DC-SIGN: Combining Chelation and Statistical Rebinding with Structural Plasticity of the Receptor

Popis výsledku anglicky

The C-type lectin receptor DC-SIGN has been highlighted as the coreceptor for the spike protein of the SARS-CoV-2 virus. A multivalent glycomimetic ligand, Polyman26, has been found to inhibit DC-SIGN-dependent trans-infection of SARS-CoV-2. The molecular details underlying avidity generation in such systems remain poorly characterized. In an effort to dissect the contribution of the known multivalent effects ─ chelation, clustering, and statistical rebinding ─ we studied a series of dendrimer constructs related to Polyman26 with a rod core rationally designed to engage simultaneously two binding sites of the tetrameric DC-SIGN. Binding properties of these compounds have been studied with a range of biophysical techniques, including recently developed surface plasmon resonance oriented-surface methodology. Using molecular modeling we addressed, for the first time, the impact of the carbohydrate recognition domains’ flexibility of the DC-SIGN tetramer on the compounds’ avidity. We were able to gain deeper insight into the role of different binding modes, which in combination produce a construct with a nanomolar affinity despite a limited valency. This multifaceted experimental–theoretical approach provides detailed understanding of multivalent ligand/multimeric protein interactions which can lead to future predictions. This work opens the way to the development of new virus attachment blockers adapted to different C-type lectin receptors of viruses.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

<a href="/cs/project/EF16_019%2F0000729" target="_blank" >EF16_019/0000729: Chemická biologie pro vývoj nových terapií</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ACS Central Science

ISSN

2374-7943

e-ISSN

2374-7951

Svazek periodika

9

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

10

Strana od-do

709-718

Kód UT WoS článku

000936010700001

EID výsledku v databázi Scopus

2-s2.0-85148876593