Kc Yuvraj, Singh Aradhana, Datta Sayantani, Das Ritika, Saxena Pranjal Raj, Chapagain Subash, Nitz T J, Wild Carl, Gaur Ritu
Virology Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University (SAU), New Delhi, 110068, India.
DFH Pharma, Gaithersburg, MD, 20886, USA.
Virol J. 2025 Jan 29;22(1):20. doi: 10.1186/s12985-025-02635-8.
Maturation inhibitors (MIs) block HIV-1 maturation by preventing the cleavage of the capsid protein and spacer peptide 1 (CA-SP1). Bevirimat (BVM), a first-in-class MI, displayed sub-optimal efficacy in clinical trials due to presence of SP1:V7A polymorphism in the Gag protein.This polymorphism is inherently present in HIV-1 subtype C and conferred resistance to BVM. Second generation BVM analogs with modifications at C-28 position gained potent activity against HIV-1 subtype C. In this study, we have evaluated the efficacy of nine second-generation MIs (BVM analogs) with varying length of C28 carbon linker against HIV-1 subtype B and C. Increasing the length of carbon linker decreased their activity against both subtypes. These MIs were also active against integrase inhibitor-resistant viruses and protease inhibitor-resistant viruses. Our data has provided vital information that in addition to the nature of the functional group at C28 position of the MI, the length of linker contributes significantly to its activity. The shorter the length, the better the activity of MIs. These results will further pave way for design of novel and potent MIs.
成熟抑制剂（MIs）通过阻止衣壳蛋白和间隔肽1（CA-SP1）的切割来阻断HIV-1的成熟。第一代成熟抑制剂贝维拉夸（BVM）在临床试验中显示出次优疗效，原因是Gag蛋白中存在SP1:V7A多态性。这种多态性天然存在于HIV-1 C亚型中，并赋予了对BVM的抗性。在C-28位进行修饰的第二代BVM类似物对HIV-1 C亚型具有强效活性。在本研究中，我们评估了9种具有不同长度C28碳连接子的第二代成熟抑制剂（BVM类似物）对HIV-1 B亚型和C亚型的疗效。增加碳连接子的长度会降低它们对这两种亚型的活性。这些成熟抑制剂对整合酶抑制剂耐药病毒和蛋白酶抑制剂耐药病毒也有活性。我们的数据提供了重要信息，即除了成熟抑制剂C28位官能团的性质外，连接子的长度对其活性也有显著贡献。连接子越短，成熟抑制剂的活性越好。这些结果将进一步为新型强效成熟抑制剂的设计铺平道路。
