2025-12-16 東京科学大学
図1. HIVの細胞への侵入機構とCD4ミミックおよび中和抗体によるブロック。
2)の構造変化に伴いHIV外被タンパク質gp120のV3ループが露出する。1)から2)への進行(1つ目の矢印)をCD4ミミックがブロックし、2)から3)への進行(2つ目の矢印)を中和抗体がブロックする。四角内に記載した、この2種の薬剤のコンジュゲート分子ADCは、効果的にHIVの細胞への侵入をブロックする。
<関連情報>
- https://www.isct.ac.jp/ja/news/neuev9cf5073
- https://www.isct.ac.jp/plugins/cms/component_download_file.php?type=2&pageId=&contentsId=1&contentsDataId=2853&prevId=&key=a30d6b8f78b8f7cc8fe76e7d2ae95845.pdf
- https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01552
CD4ミミックと中和抗体を用いたHIV-1侵入阻害剤としての抗体薬物複合体 Antibody-Drug Conjugates Using CD4 Mimics and a Neutralizing Antibody as HIV-1 Entry Inhibitors
Yutaro Miura,Kohei Tsuji,Takuya Kobayakawa,Kaho Matsumoto,Takeo Kuwata,Riku Matsuzaki,Shuzo Matsushita,and Hirokazu Tamamura
Journal of Medicinal Chemistry Published: December 15, 2025
DOI:https://doi.org/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.
