Dendrimer-Peptide Conjugates for Effective Blockade of the Interactions between SARS-CoV-2 Spike Protein and Human ACE2 Receptor

Woo Jin Jeong, Jiyoon Bu, Philip Mickel, Yanxiao Han, Piper A. Rawding, Jianxin Wang, Hanbit Kang, Heejoo Hong, Petr Král, Seungpyo Hong

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)141-149
Number of pages9
Issue number1
Publication statusPublished - 2023 Jan 9

Bibliographical note

Funding Information:
This study was partially supported by National Science Foundation (NSF) under grant # DMR-1808251 and 2211932. The authors also acknowledge the partial support from the Wisconsin Head & Neck Cancer SPORE Grant from NIH (P50-DE026787), The Falk Medical Research Trust – Catalyst and Transformational Awards Program, and Milton J. Henrichs Chair Funds. Partial support from the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (2021R1C1C1009912, 2021R1A4A3024237) is also acknowledged.

Publisher Copyright:
© 2022 American Chemical Society.

All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Biomaterials
  • Polymers and Plastics
  • Materials Chemistry


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