Abstract
Virus inactivator can inactivate cell-free virions without relying on their replication cycle, potentially reducing the impact of viral infection on cells. 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. Therefore, it targets both the CD4 binding site in gp120 and NHR region in 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). The results showed that FD028 inactivated cell-free virions at a moderate nanomolar concentration by targeting both HIV-1 gp120 and gp41. Moreover, FD028 has broad-spectrum inhibition and inactivation activity against HIV-1 resistant strains and primary isolates of different subtypes without significant cytotoxicity. Therefore, FD028 has potential for further development as an HIV-1 inactivator-based therapeutic.
Highlights
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)
NBD-556 analog FD016 was synthesized from N-(4-chloro-3fluorophenyl) oxalamic acid ethyl ester 1 (Narumi et al, 2013) as starting material following the previously reported method (Debnath et al, 2006)
For the preparation of gp41-targeting compound FD017, N-substituted rhodanine 4 was first synthesized by a literature procedure (Radi et al, 2010a), and tyramine 3 was treated with bis(carboxymethyl) trithiocarbonate in i-PrOH at 90°C in a microwave for 45 min to give 4 in 84% yield
Summary
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). Inhibitors approved by the U.S 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 (https://www.fda.gov). Fusion inhibitors acting on the virus-cell fusion stage may have unique advantages in maintaining normal physiological functions of cells and inhibiting viral infection. All of these inhibitors rely on the existence of cells to exert their antiviral activity and cannot actively
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