ABSTRACT
From the process of human immunodeficiency virus-1 (HIV-1) invading cells, the combination of gp120 and CD4 is the first step for HIV-1 to invade cells. Interfering with this process can prevent HIV from recognizing target cells and inhibit virus replication. Therefore, HIV-1 gp120 is an important part of the HIV-1 life cycle. Fostesavir, a phosphatate prodrug derived from the gp120 inhibitor BMS-626529 modified by the prodrug strategy, was approved for the treatment of adult patients with multidrug resistant HIV-1 infection by the US FDA and the European Medicines Agency in 2020 and 2021, respectively. In this review, we focus on the research progress of small molecule inhibitors targeting the interaction of gp120-CD4 from the perspective of medicinal chemistry, in order to provide reference for the subsequent research of gp120 inhibitors.
ABSTRACT
The envelope glycoprotein subunit gp120 and the transmembrane subunit gp41 of human immunodeficiency virus type 1(HIV-1)play important roles in the process of viral entry into target cells, and serve as key targets for developing HIV-1 entry inhibitors. Peptide HIV entry inhibitors, such as T20, are limited in clinical application due to the lack of oral properties. However, because of the possible oral administration and high bioavailability, small molecule compounds become more and more important in the research for HIV entry inhibitors. In this review, we summarize the recent advances in the development of small molecule HIV-1 entry inhibitors, including the NBD and BMS series of small-molecule inhibitors targeting gp120 as well as the NB-206 and ADS-J1 se- ries of small-molecule inhibitors targeting gp41. These small molecule inhibitors are promising compounds with research value, which lay a foundation for the design of more efficient and more reasonable small-molecule HIV-1 entry inhibitors.
ABSTRACT
Arenaviruses are enveloped RNA viruses, and eight members in this family are known to cause human hemorrhagic fever. Treatments for the viral hemorrhagic fever (VHF) by arenaviruses are very limited. We have identified the first flavone, tangeretin, with broad-spectrum inhibitory activities on VHF-arenaviruses infection by blocking viral entry. In this study, we evaluated thirty-four tangeretin analogues and found 3,5,6,7,4'-pentamethoxyflavone as a Lassa virus entry inhibitor, with EC50 of 5.2 µmol·L-1, by blocking the viral fusion process. The compound 3,5,6,7,4'-pentamethoxyflavone is effective on all known VHF-arenaviruses, with EC50 range of 0.84-10.2 µmol·L-1. These results suggest that 3,5,6,7,4'-pentamethoxyflavone is able to serve as a start point for discovery of arenavirus entry inhibitors from flavone natural products.
ABSTRACT
Arenaviruses are enveloped RNA viruses. The genus mammarenavirus contains nine members that are known to be human pathogens, and eight of them cause human hemorrhagic fever. Lassa hemorrhagic fever, caused by Lassa virus (LASV) infection, is the most prevalent arenavirus hemorrhagic fever with potential to cause major epidemics. LASV belongs to category A agents, and biosafety level-4 (BSL-4) facility is required for live virus experiments. Currently there are few specific treatments available for arenavirus diseases. Here, we established efficient cell-based pseudovirus infection models using an HIV-1 core (pNL4-3.Luc.R-E-) packed with arenavirus glycoproteins. Nine recombinant arenaviruses (arenavirus-GP/HIV-luc) were generated, and 17 cell lines were tested for susceptibilities to these viruses. These pseudovirus infection models were further validated by known arenavirus entry inhibitors. The models are safe and specific to pseudovirus infection, which are readily used for pharmacodynamic evaluation of arenavirus entry inhibitors in BSL-2 laboratory. The models will facilitate screening of the anti-arenavirus drugs and vaccines.
ABSTRACT
Aim To study the inhibitory activities of potential new anti-influenza virus agents,3-O-β-chaco-triosyl pentacyclic triterpenoids against the entry of H5N1influenza viruses.Methods Three target com-pounds were designed and synthesized structurally re-lated to the lead compound 3-O-β-chacotriosyl dioscin derivative (1 )with inhibitory activities against H5N1 influenza viruses.The inhibitory activities of these tar-get compounds were tested at a cellular level pseudo vi-rus system targeting H5N1 influenza viruse entry.Re-sults All the compounds 1 a,1 b and 1 c showed po-tent inhibitory activities against the entry of A/Thai-land/Kan353/2004 pseudo virus into the target cells, of which compound 1 b showed the best inhibitory activ-ity with an IC50 value of (1.25 ±0.22)μmol·L-1. Conclusion The SARs analysis of these compounds indicated that replacement of the aglycone moiety of compound 1 with pentacyclic triterpenoids could in-crease antiviral activity.Different types of pentacyclic triterpen as aglycone residue had the significant influ-ence on the inhibitory activity (1 b >1 c >1 a),sug-gesting ursane type of triterpenes was superior to the two other kinds of triterpenes as aglycone residue.
ABSTRACT
Aim ADS-J1 is a low molecular HIV entry inhibitor targeting HIV transmembrane subunit gp41 through virtual screening from a compound library containing 20 000 molecules.This study is to investigate the binding sites of ADS-J1 on gp41.Methods Acid native polyacrylamide gel electrophoresis (AN-PAGE) assay was applied to test the binding ability of ADS-J1 with the peptides derived from gp41 N-terminal heptad repeat (NHR) region.Results It was reported previously that ADS-J1 could block the gp41 six-helix bundle (6-HB) formation using native polyacrylamide gel electrophoresis (N-PAGE).However,the binding sites could not be found because positive charged N-peptides derived from gp41 NHR could not show bands on the gel.In the present study,the AN-PAGE assay which could show N-peptides in the gel was established,and it was found that ADS-J1 could inhibit the gp41 6-HB formation.Moreover,ADS-J1 bound directly to the gp41 cavity region of NHR.The positively charged residue (K574) located in this region was critical for the binding of ADS-J1.Conclusions ADS-J1 inhibits HIV entry by targeting the cavity region of gp41 NHR,whereas K574 in the cavity plays a critical role for the binding.Furthermore,the AN-PAGE assay provides a simple method for studying the mechanism of action of virus entry inhibitors targeting the transmembrane protein of type I enveloped virus.
ABSTRACT
Hepatitis C virus (HCV) is a member of the Flaviviridae family and causes acute and chronic hepatitis. Chronic HCV infection may result in severe liver damage including liver cirrhosis and hepatocellular carcinoma. The liver is the primary target organ of HCV, and the hepatocyte is its primary target cell. Attachment of the virus to the cell surface followed by viral entry is the first step in a cascade of interactions between the virus and the target cell that is required for successful entry into the cell and initiation of infection. This step is an important determinant of tissue tropism and pathogenesis; it thus represents a major target for antiviral host cell responses, such as antibody-mediated virus neutralization. Following the development of novel cell culture models for HCV infection our understanding of the HCV entry process and mechanisms of virus neutralization has been markedly advanced. In this review we summarize recent developments in the molecular biology of viral entry and its impact on pathogenesis of HCV infection, development of novel preventive and therapeutic antiviral strategies.