The development of over 20 antiretroviral drugs has led to efficient and successful suppression of HIV-1 replication. In addition to common viral targets, such as reverse transcriptase and protease, new targets have been recently exploited, including integrase, fusion and cellular CCR5. Hence, combination antiretroviral therapy is continually improved by the development of these new agents, especially for patients infected with drug-resistant HIV-1. In this review, we focused on fusion inhibitory peptides that have been developed since the first HIV-1 fusion inhibitor, enfuvirtide (T-20). T-20, approved for clinical use in 2003, is a polypeptide comprising 36 amino acids derived from the HIV-1 gp41 C-terminal heptad repeat and provides a novel treatment strategy for HIV-1 therapy. T-20 is able to suppress HIV-1 replication, including viruses resistant to reverse transcriptase or protease inhibitors. However, after prolonged T-20-containing treatment regimens, HIV-1 acquires resistance to T-20. Therefore, our laboratory and others have developed novel fusion inhibitors, termed next-generation fusion inhibitors, including electrostatically constrained, mutation introduced, and trimer-form peptides.
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