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In the treatment of viral infectious diseases, there are dominantly fewer examples of ADCs. Recently, we developed double\u2010warhead ADCs targeting the entry of human immunodeficiency virus type 1 (HIV\u20101) into host cells. One is a small molecule CD4 mimic, which is a competitive inhibitor against the interaction between a viral envelop protein, gp120, and a primary receptor, CD4, and the other is neutralizing antibodies, which recognize the regions of gp120, exposed by its conformational change after the interaction between gp120 and CD4. The conformational changes are also triggered by the binding of gp120 and a CD4 mimic, and therefore, the ADCs show positive effects on anti\u2010HIV\u20101 activity compared to the combinational use of CD4 mimics with neutralizing antibodies. Herein, we synthesized novel ADCs containing a CD4 mimic and a neutralizing antibody, KD\u2010247, using tCAP chemistry, which is based on a site\u2010specific modification method for IgG antibodies, and evaluated their anti\u2010HIV\u20101 and antibody\u2010dependent cellular cytotoxicity (ADCC) activities. As a result, the KD\u2010247\u2010adopted ADCs demonstrated enhanced anti\u2010HIV\u20101 activities, whereas all of the ADCs reduced their ADCC activities.<\/jats:p>","DOI":"10.1002\/cmdc.202500820","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T17:32:53Z","timestamp":1770917573000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD4 Mimic\u2010Neutralizing Antibody Conjugates Synthesized by Site\u2010Specific Modification Methods as HIV\u20101 Entry Inhibitors"],"prefix":"10.1002","volume":"21","author":[{"given":"Kohei","family":"Tsuji","sequence":"first","affiliation":[{"name":"Laboratory for Biomaterials and Bioengineering Institute of Integrated Research Institute of Science Tokyo Chiyoda\u2010ku Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutaro","family":"Miura","sequence":"additional","affiliation":[{"name":"Laboratory for Biomaterials and Bioengineering Institute of Integrated Research Institute of Science Tokyo Chiyoda\u2010ku Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeo","family":"Kuwata","sequence":"additional","affiliation":[{"name":"The Joint Research Center for Human Retrovirus Infection Kumamoto University  Kumamoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riku","family":"Matsuzaki","sequence":"additional","affiliation":[{"name":"Laboratory for Biomaterials and Bioengineering Institute of Integrated Research Institute of Science Tokyo Chiyoda\u2010ku Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuya","family":"Kobayakawa","sequence":"additional","affiliation":[{"name":"Laboratory for Biomaterials and Bioengineering Institute of Integrated Research Institute of Science Tokyo Chiyoda\u2010ku Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaho","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"The Joint Research Center for Human Retrovirus Infection Kumamoto University  Kumamoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Ito","sequence":"additional","affiliation":[{"name":"Graduate School of Science and Engineering Kagoshima University  Kagoshima Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taku","family":"Yoshiya","sequence":"additional","affiliation":[{"name":"Peptide Institute, Inc.  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