Glycan-binding properties of SARS-CoV-2 spike proteins: interactions with aminoglycoside antibiotics

  • Sci Rep. 2026 Mar 9;16(1):12769. doi: 10.1038/s41598-026-42404-3.
Dai Hatakeyama  1  2 ,  Masaki Shoji  1 ,  Yusuke Miki  1 ,  Shoji Ueki  3 ,  Kentaro Yamaguchi  3 ,  Katsuyuki Nakashima  1 ,  Yoshiyuki Tanaka  1 ,  Mariko Yokogawa  4 ,  Masanori Osawa  4 ,  Yusuke Kasai  1 ,  Hiroshi Imagawa  1 ,  Rina Hashimoto  5  6 ,  Kazuo Takayama  5  6 ,  Takashi Kuzuhara  7
Affiliations
  • 1. Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
  • 2. Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan.
  • 3. Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Takamatsu, Japan.
  • 4. Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
  • 5. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
  • 6. Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan.
  • 7. Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan. [email protected].
PMID: 41803230 DOI: 10.1038/s41598-026-42404-3
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells via its spike (S) protein, which binds to the angiotensin-converting enzyme 2 (ACE2) receptor. Glycans are thought to influence this interaction by modulating the binding affinity between the S protein and its receptor. In this study, we screened 300 carbohydrate species using a glycan array to identify potential ligands that interact with the S proteins of the Delta and Omicron variants. Among the identified candidates, two Aminoglycoside antibiotics, tobramycin and sisomicin, exhibited notable binding to the S protein. Surface plasmon resonance (SPR), circular dichroism (CD), and in silico docking analyses confirmed direct interactions between these aminoglycosides and the S protein, revealing distinct binding characteristics. Nuclear magnetic resonance (NMR) analysis further localized the tobramycin-binding site within the receptor-binding domain (RBD) of the S protein. Tobramycin and sisomicin showed a tendency to inhibit SARS-CoV-2 replication in human induced pluripotent stem cell (hiPSC)-derived lung organoids, though the effect did not reach statistical significance. Docking simulations using the trimeric S model suggested that aminoglycosides bind at an inter-subunit interface. These findings demonstrate that aminoglycosides can directly interact with the SARS-CoV-2 S Protein and may serve as scaffolds for developing host-independent Antiviral agents against SARS-CoV-2 and its variants.

Keywords
Aminoglycoside antibiotics; Glycan array; SARS-CoV-2; Sisomicin; Spike protein; Tobramycin.
Products