Antibody-Drug Conjugates Using CD4 Mimics and a Neutralizing Antibody as HIV-1 Entry Inhibitors

  • J Med Chem. 2025 Dec 25;68(24):25899-25911. doi: 10.1021/acs.jmedchem.5c01552.
Yutaro Miura  1 ,  Kohei Tsuji  1 ,  Takuya Kobayakawa  1 ,  Kaho Matsumoto  2 ,  Takeo Kuwata  2 ,  Riku Matsuzaki  1 ,  Shuzo Matsushita  2 ,  Hirokazu Tamamura  1
Affiliations
  • 1. Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
  • 2. Collaborative Research Program with the Chemo-Sero-Therapeutic Research Institute for Anti-viral Agents and Hematological Diseases, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 5-1 Oe Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
PMID: 41395826 DOI: 10.1021/acs.jmedchem.5c01552
Abstract

The development of new anti-HIV drugs with a novel mechanism of action is still required. A human cell surface protein, CD4, is a primary receptor for HIV-1 entry, and we have developed small-molecule CD4-competitive HIV-1 entry inhibitors, including CD4 mimics. CD4 mimics bind to a viral envelope protein, gp120, and cause a conformational change. Combinational use of CD4 mimics with CD4-induced antibodies, which recognize the exposed regions of gp120 induced by the CD4/CD4 mimic binding, shows a synergistic effect of anti-HIV activity. Therefore, we envisioned that antibody-drug conjugates (ADCs) of CD4 mimics and CD4-induced antibodies would effectively inhibit virus entry. Herein, ADCs of CD4 mimics and CD4-induced antibodies were designed and synthesized, and their anti-HIV-1 activities were evaluated. As a result, several synthesized ADCs exhibited 7- to 10-fold higher anti-HIV-1 activity than that of the parent antibodies, although there remains significant room for improvement in these ADCs.

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