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The long-standing fight against HIV-1 infection still faces significant challenges in achieving effective disease control. Extensive efforts to develop drugs targeting integrase (IN) have culminated in the approval of five strand transfer inhibitors (INSTIs) over the past 15 years, marking a major milestone in antiretroviral therapy. While INSTIs remain the cornerstone of HIV treatment, concerns about resistance have demanded ongoing research to discover diverse antiretroviral agents with higher genetic barrier to resistance. This impelling need has driven the exploration of innovative strategies to inhibit HIV-1 IN through alternative mechanisms. In this context, prominent efforts have focused on HIV-1 IN allosteric inhibitors (ALLINIs), a promising class of antiretroviral agents that have recently advanced in clinical trials. Recent elucidation of the structural and mechanistic features of IN and its inhibitors has revealed additional allosteric pockets and new functional roles of IN in HIV-1 biology, offering valuable insights and significant opportunities for the development of novel inhibitors. This chapter offers a historical sketch and a detailed overview of the innovative strategies employed to target HIV-1 IN through small molecules. By integrating medicinal chemistry, structural, and mechanistic insights, it provides a comprehensive perspective on the pursuit of novel antiretroviral agents targeting HIV-1 IN.

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HIV-1 Integrase During the Time: History of Drugs and Effort for the New Inhibitors’ Identification

  • 章节

  • 发表日期：

    2026年

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  • Francesca Esposito,
  • Francesco Saccoliti,
  • Elisa Patacchini,
  • Roberto Di Santo

摘要

The long-standing fight against HIV-1 infection still faces significant challenges in achieving effective disease control. Extensive efforts to develop drugs targeting integrase (IN) have culminated in the approval of five strand transfer inhibitors (INSTIs) over the past 15 years, marking a major milestone in antiretroviral therapy. While INSTIs remain the cornerstone of HIV treatment, concerns about resistance have demanded ongoing research to discover diverse antiretroviral agents with higher genetic barrier to resistance. This impelling need has driven the exploration of innovative strategies to inhibit HIV-1 IN through alternative mechanisms. In this context, prominent efforts have focused on HIV-1 IN allosteric inhibitors (ALLINIs), a promising class of antiretroviral agents that have recently advanced in clinical trials. Recent elucidation of the structural and mechanistic features of IN and its inhibitors has revealed additional allosteric pockets and new functional roles of IN in HIV-1 biology, offering valuable insights and significant opportunities for the development of novel inhibitors. This chapter offers a historical sketch and a detailed overview of the innovative strategies employed to target HIV-1 IN through small molecules. By integrating medicinal chemistry, structural, and mechanistic insights, it provides a comprehensive perspective on the pursuit of novel antiretroviral agents targeting HIV-1 IN.