Investigating vulnerability of the conserved SARS-CoV-2 spike's heptad repeat 2 as target for fusion inhibitors using chimeric miniproteins
Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved..
Inhibition of SARS-CoV-2 membrane fusion is a highly desired target to combat COVID-19. The interaction between the spike's heptad repeat (HR) regions 1 (HR1) and 2 (HR2) is a crucial step during the fusion process and these highly conserved HR regions constitute attractive targets for fusion inhibitors. However, the relative importance of each subregion of the long HR1-HR2 interface for viral inhibition remains unclear. Here, we designed, produced, and characterized a series of chimeric miniproteins that mimic two different half subdomains of HR1. The proteins were designed as single polypeptide chains that spontaneously fold into antiparallel trimeric helical bundles aimed at structurally imitate the molecular surface of each HR1 half subregion. All the miniproteins folded stably as helical structures and could bind complementary HR2 peptides with moderate affinity. However, only the miniproteins mimicking the N-terminal HR1 half subdomain, but not those imitating C-terminal one, could inhibit cell infection by SARS-COV-2 real viruses in cell cultures. Most interestingly, the inhibitory activity of the miniproteins correlated with their structural stability, but not with their relative binding affinity for HR2 peptides. These results are highly relevant for designing more focused and active fusion inhibitors targeting the highly conserved HR2 region of the Spike.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:262 |
|---|---|
| Enthalten in: |
International journal of biological macromolecules - 262(2024), Pt 2 vom: 25. März, Seite 130132 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Polo-Megías, Daniel [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Anti-Retroviral Agents |
|---|
| Anmerkungen: |
Date Completed 27.03.2024 Date Revised 27.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.ijbiomac.2024.130132 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM368450201 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM368450201 | ||
| 003 | DE-627 | ||
| 005 | 20240327235815.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240215s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.ijbiomac.2024.130132 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1351.xml |
| 035 | |a (DE-627)NLM368450201 | ||
| 035 | |a (NLM)38354919 | ||
| 035 | |a (PII)S0141-8130(24)00935-8 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Polo-Megías, Daniel |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Investigating vulnerability of the conserved SARS-CoV-2 spike's heptad repeat 2 as target for fusion inhibitors using chimeric miniproteins |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 27.03.2024 | ||
| 500 | |a Date Revised 27.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a Inhibition of SARS-CoV-2 membrane fusion is a highly desired target to combat COVID-19. The interaction between the spike's heptad repeat (HR) regions 1 (HR1) and 2 (HR2) is a crucial step during the fusion process and these highly conserved HR regions constitute attractive targets for fusion inhibitors. However, the relative importance of each subregion of the long HR1-HR2 interface for viral inhibition remains unclear. Here, we designed, produced, and characterized a series of chimeric miniproteins that mimic two different half subdomains of HR1. The proteins were designed as single polypeptide chains that spontaneously fold into antiparallel trimeric helical bundles aimed at structurally imitate the molecular surface of each HR1 half subregion. All the miniproteins folded stably as helical structures and could bind complementary HR2 peptides with moderate affinity. However, only the miniproteins mimicking the N-terminal HR1 half subdomain, but not those imitating C-terminal one, could inhibit cell infection by SARS-COV-2 real viruses in cell cultures. Most interestingly, the inhibitory activity of the miniproteins correlated with their structural stability, but not with their relative binding affinity for HR2 peptides. These results are highly relevant for designing more focused and active fusion inhibitors targeting the highly conserved HR2 region of the Spike | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a Calorimetry | |
| 650 | 4 | |a Thermal stability | |
| 650 | 7 | |a Viral Envelope Proteins |2 NLM | |
| 650 | 7 | |a Spike Glycoprotein, Coronavirus |2 NLM | |
| 650 | 7 | |a Peptides |2 NLM | |
| 650 | 7 | |a Anti-Retroviral Agents |2 NLM | |
| 650 | 7 | |a spike protein, SARS-CoV-2 |2 NLM | |
| 700 | 1 | |a Cano-Muñoz, Mario |e verfasserin |4 aut | |
| 700 | 1 | |a Berruezo, Alberto G |e verfasserin |4 aut | |
| 700 | 1 | |a Laumond, Géraldine |e verfasserin |4 aut | |
| 700 | 1 | |a Moog, Christiane |e verfasserin |4 aut | |
| 700 | 1 | |a Conejero-Lara, Francisco |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t International journal of biological macromolecules |d 1992 |g 262(2024), Pt 2 vom: 25. März, Seite 130132 |w (DE-627)NLM012627356 |x 1879-0003 |7 nnns |
| 773 | 1 | 8 | |g volume:262 |g year:2024 |g number:Pt 2 |g day:25 |g month:03 |g pages:130132 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.ijbiomac.2024.130132 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 262 |j 2024 |e Pt 2 |b 25 |c 03 |h 130132 | ||