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

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.