Design, identification and development of novel antiviral agents active against HIV

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In this project, we identified several novel anti-HIV-agents active against multi-drug resistant HIV (HIV_<MDR>). UIC96003 is a novel PI that contains a unique bis-tetrahydrofuranyl-urethane and exerts potent activity against a wide spectrum of HIV_<MDR> strains (Yoshimura & Mitsuya, J.Virol. 76:1349-58,2002). UIC-96003's derivative, UIC94017/TMC114 (Koh & Mitsuya, AAC. 47:3123-29,2003), is now in Phase II clinical trials in the Europe. We also identified novel spirodiketopiperazine (SDP)-containing CCR5 inhibitors such as AK602/ON04128/GW873140, which exerted potent activity against R5-HIV. AK602 potently blocks HIV gp120 binding to CCR5 and suppresses HIV infection, but only moderately inhibits CC-chemokine RANTES binding to CCR5 (Maeda & Mitsuya, J.Virol. in press), in agreement with our observation that anti-HIV acitivity and the function of CC-chemokines are not always correlated (Miyakawa & Mitsuya, JBC. 277:4649-55,2002). AK602 has proved to have favorable pharmacokinetic profiles and now has been in Phase II clinical trial in the US.In the other area of research, we identified novel mechanisms of the emergence of resistance against existing reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs). In particular, we demonstrated the pathways of the emergence of multi-NRTI-resistant HIV variants (Matsumi & Mitsuya, AIDS 17:1-11,2003) and reported that certain mutations in HIV's Gag are linked with high levels of viral resistance agianst multiple PIs (Gatanaga & Mitsuya, JBC. 277:5952-61,2002).