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Dendrimer-Peptide Conjugates for Effective Blockade of the Interactions between SARS-CoV-2 Spike Protein and Human ACE2 Receptor.
Jeong, Woo-Jin; Bu, Jiyoon; Mickel, Philip; Han, Yanxiao; Rawding, Piper A; Wang, Jianxin; Kang, Hanbit; Hong, Heejoo; Král, Petr; Hong, Seungpyo.
  • Jeong WJ; Pharmaceutical Sciences Division, The University of Wisconsin-Madison, 777 Highland Ave., Madison, Wisconsin 53705, United States.
  • Bu J; Wisconsin Center for NanoBioSystems, The University of Wisconsin-Madison, 777 Highland Ave., Madison, Wisconsin 53705, United States.
  • Mickel P; Department of Biological Sciences and Bioengineering, Inha University, 100 Inha-ro, Michuhol-gu, Incheon 22212, Korea.
  • Han Y; Pharmaceutical Sciences Division, The University of Wisconsin-Madison, 777 Highland Ave., Madison, Wisconsin 53705, United States.
  • Rawding PA; Wisconsin Center for NanoBioSystems, The University of Wisconsin-Madison, 777 Highland Ave., Madison, Wisconsin 53705, United States.
  • Wang J; Department of Biological Sciences and Bioengineering, Inha University, 100 Inha-ro, Michuhol-gu, Incheon 22212, Korea.
  • Kang H; Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, United States.
  • Hong H; Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, United States.
  • Král P; Pharmaceutical Sciences Division, The University of Wisconsin-Madison, 777 Highland Ave., Madison, Wisconsin 53705, United States.
  • Hong S; Wisconsin Center for NanoBioSystems, The University of Wisconsin-Madison, 777 Highland Ave., Madison, Wisconsin 53705, United States.
Biomacromolecules ; 24(1): 141-149, 2023 01 09.
Article in English | MEDLINE | ID: covidwho-2185444
ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic has threatened the stability of global healthcare, which is becoming an endemic issue. Despite the development of various treatment strategies to fight COVID-19, the currently available treatment options have shown varied efficacy. Herein, we have developed an avidity-based SARS-CoV-2 antagonist using dendrimer-peptide conjugates (DPCs) for effective COVID-19 treatment. Two different peptide fragments obtained from angiotensin-converting enzyme 2 (ACE2) were integrated into a single sequence, followed by the conjugation to poly(amidoamine) (PAMAM) dendrimers. We hypothesized that the strong multivalent binding avidity endowed by dendrimers would help peptides effectively block the interaction between SARS-CoV-2 and ACE2, and this antagonist effect would be dependent upon the generation (size) of the dendrimers. To assess this, binding kinetics of the DPCs prepared from generation 4 (G4) and G7 PAMAM dendrimers to spike protein of SARS-CoV-2 were quantitatively measured using surface plasmon resonance. The larger dendrimer-based DPCs exhibited significantly enhanced binding strength by 3 orders of magnitude compared to the free peptides, whereas the smaller one showed a 12.8-fold increase only. An in vitro assay using SARS-CoV-2-mimicking microbeads also showed the improved SARS-CoV-2 blockade efficiency of the G7-peptide conjugates compared to G4. In addition, the interaction between the DPCs and SARS-CoV-2 was analyzed using molecular dynamics (MD) simulation, providing an insight into how the dendrimer-mediated multivalent binding effect can enhance the SARS-CoV-2 blockade. Our findings demonstrate that the DPCs having strong binding to SARS-CoV-2 effectively block the interaction between ACE2 and SARS-CoV-2, providing a potential as a high-affinity drug delivery system to direct anti-COVID payloads to the virus.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Dendrimers / COVID-19 Type of study: Experimental Studies Limits: Humans Language: English Journal: Biomacromolecules Journal subject: Molecular Biology Year: 2023 Document Type: Article Affiliation country: Acs.biomac.2c01018

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Dendrimers / COVID-19 Type of study: Experimental Studies Limits: Humans Language: English Journal: Biomacromolecules Journal subject: Molecular Biology Year: 2023 Document Type: Article Affiliation country: Acs.biomac.2c01018