In addition, reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors do not block virions from cell entry. However, inhibitors that target host proteins may affect the normal physiological functions of cells. Food and Drug Administration (FDA) for clinical treatment of HIV-1/AIDS (acquired immunodeficiency syndrome) and their combination treatments mainly target the host protein or virus-cell fusion process or the stage after virus entry ( ). Type I human immunodeficiency virus (HIV-1) infection target cells mainly undergo CD4 receptor binding, co-receptor (CXCR4/CCR5) binding, membrane fusion, reverse transcription, DNA integration and protein synthesis ( Fanales-Belasio et al., 2010). Therefore, FD028 has potential for further development as an HIV-1 inactivator-based therapeutic. Moreover, FD028 has broad-spectrum inhibition and inactivation activity against HIV-1 resistant strains and primary isolates of different subtypes without significant cytotoxicity. The results showed that FD028 inactivated cell-free virions at a moderate nanomolar concentration by targeting both HIV-1 gp120 and gp41.
Considering that small-molecule agents have the advantages of fast production, low cost, good stability, and oral availability, we herein report the design of a new small-molecule HIV-1 inactivator, FD028, by conjugating FD016 (an analog of NBD-556, a gp120-CD4 binding inhibitor) with FD017 (an analog of 11d, an HIV-1 fusion inhibitor). Therefore, it targets both the CD4 binding site in gp120 and NHR region in gp41.
Previously, we successfully constructed a HIV-1 protein inactivator, 2DLT, by conjugating the D1D2 region of CD4 to the fusion inhibitor T1144 via a 35-amino acid linker. Virus inactivator can inactivate cell-free virions without relying on their replication cycle, potentially reducing the impact of viral infection on cells. 6Beijing Institute of Pharmacology and Toxicology, Beijing, China.5Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.4College of Life Sciences, Hebei Agricultural University, Baoding, China.3Beijing Institute of Radiation Medicine, Beijing, China.Kimball Research Institute, New York Blood Center, New York, NY, United States 1Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.Jing Pu 1,2 †, Yu Dai 3,4 †, Qian Wang 1 †, Lu Lu 1, Junqi Zhang 5, Wei Xu 1, Lan Xie 6, Shengqi Wang 3, Fei Yu 4*, Xiaoyang He 3* and Shibo Jiang 1,2*