2. Academic Validation
  3. Impact of Single Halogen Atom Substitutions on Antiviral Profile of Inhibitors Targeting SARS-CoV‑2 Main Protease

Impact of Single Halogen Atom Substitutions on Antiviral Profile of Inhibitors Targeting SARS-CoV‑2 Main Protease

  • ACS Omega. 2026 Jan 14;11(3):4541-4550. doi: 10.1021/acsomega.5c10895.
Haydar Bulut 1,  Nobuyo Higashi-Kuwata 2,  Hiromi Ogata-Aoki 2 3,  Hironori Hayashi 4,  Nobutoki Takamune 5,  Naoki Kishimoto 5,  Debananda Das 1,  Mi Li 6,  Alexander Wlodawer 7,  Shogo Misumi 5,  Hirokazu Tamamura 8,  Hiroaki Mitsuya 1 2 9
Affiliations

Affiliations

  • 1 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States.
  • 2 Department of Refractory Viral Diseases, National Institute of Global Health and Medicine, Japan Institute for Health Security, Tokyo 162-8655, Japan.
  • 3 Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-8556, Japan.
  • 4 International Research Institute of Disaster Science, Tohoku University, Miyagi 980-8575, Japan.
  • 5 Department of Environmental and Molecular Health Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
  • 6 Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States.
  • 7 Laboratory of Cell Biology, National Cancer Institute, Bethesda, Maryland 20892, United States.
  • 8 Department of Medicinal Chemistry, Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Tokyo 101-0062, Japan.
  • 9 Kumamoto University Hospital, Kumamoto 860-8556, Japan.
PMID: 41626465 DOI: 10.1021/acsomega.5c10895
Abstract

The SARS-CoV-2 main protease (Mpro) remains a prime Antiviral target because its inhibition halts viral replication. To probe how subtle atomic changes influence drug performance, we carried out a systematic halogen scan on a potent ketoamide scaffold, replacing a single fluorine with chlorine, bromine, or iodine. Enzymatic assays revealed that the F- and Cl-substituted analogues inhibit Mpro at nanomolar levels, whereas Br and I variants are 10- to 20-fold weaker. Cell-based Antiviral tests mirrored this trend, yet uptake studies showed the opposite: iodine markedly enhances intracellular accumulation. High-resolution X-ray structures (1.6-1.8 Å) explain the dichotomy: small halogens fit snugly in the S1' σ-hole pocket, maximizing hydrogen-bond geometry, while bulkier atoms distort binding but create a lipophilic patch that boosts permeability. These data yield the first fluorine-to-iodine structure-activity map for SARS-CoV-2 Mpro inhibitors. These findings highlight the critical role of halogen selection in Antiviral inhibitor design.

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