A causative virus of AIDS is HIV. Currently, combination antiretroviral therapy (cART), which involves a combinational dosage of several anti-HIV drugs, is used in clinical treatment. However, because of the emergence of drug-resistant strains of HIV, significant side effects and high costs, development of novel anti-HIV drugs with different mechanisms of action is required. Thus, we have focused on anti-HIV agents that interact with several conserved regions of envelope proteins to inhibit viral entry. So far we have developed small molecule HIV entry inhibitors, CD4 mimics, to bind to an HIV envelop protein, gp120, and compete with the host cell surface protein, CD4. The binding of CD4 and CD4 mimics to gp120 induces its conformational change, and the co-receptor binding site is then exposed to be recognized by neutralizing antibodies [1]. Therefore, we envisioned that antibody-drug-conjugates (ADCs), which are composed of CD4 mimics and neutralizing antibodies, would effectively inhibit virus entry. Furthermore, the use of CD4 mimics has an advantage in safety because the co-receptor binding site can be exposed without host cell binding [2].
In this study, we synthesized several ADCs using various linker structures and lengths, and evaluated their anti-HIV activities. We used two HIV neutralizing antibodies to prepare the ADCs. Both a non-specific modification method using an active ester and site-specific conjugation methods were utilized to conjugate these antibodies and CD4 mimics. The linker length of the ADCs was adjusted by the number of linker unit repetition. As a result, significant activity improvements of the ADCs were shown, compared to that of the parent antibodies and CD4 mimics or co-treatment of them. The present concept is useful as a new chemotherapy against HIV infectious diseases.