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Entry Inhibitors (entry + inhibitor)

Distribution by Scientific Domains

Medical Sciences	40%

Selected Abstracts

Structure,function relationship of novel X4 HIV-1 entry inhibitors , L- and D-arginine peptide-aminoglycoside conjugates

FEBS JOURNAL, Issue 24 2007
Ravi Hegde
We present the design, synthesis, anti-HIV-1 and mode of action of neomycin and neamine conjugated at specific sites to arginine 6- and 9-mers d - and l -arginine peptides (APACs). The d -APACs inhibit the infectivity of X4 HIV-1 strains by one or two orders of magnitude more potently than their respective l -APACs. d -arginine conjugates exhibit significantly higher affinity towards CXC chemokine receptor type 4 (CXCR4) than their l -arginine analogs, as determined by their inhibition of monoclonal anti-CXCR4 mAb 12G5 binding to cells and of stromal cell-derived factor 1, (SDF-1,)/CXCL12 induced cell migration. These results indicate that APACs inhibit X4 HIV-1 cell entry by interacting with CXCR4 residues common to glycoprotein 120 and monoclonal anti-CXCR4 mAb 12G5 binding. d -APACs readily concentrate in the nucleus, whereas the l -APACs do not. 9-mer- d -arginine analogues are more efficient inhibitors than the 6-mer- d -arginine conjugates and the neomycin- d -polymers are better inhibitors than their respective neamine conjugates. This and further structure,function studies of APACs may provide new target(s) and lead compound(s) of more potent HIV-1 cell entry inhibitors. [source]

Characterization of host-range and cell entry properties of the major genotypes and subtypes of hepatitis C virus,

HEPATOLOGY, Issue 2 2005
Dimitri Lavillette
Because of the lack of a robust cell culture system, relatively little is known about the molecular details of the cell entry mechanism for hepatitis C virus (HCV). Recently, we described infectious HCV pseudo-particles (HCVpp) that were generated by incorporating unmodified HCV E1E2 glycoproteins into the membrane of retroviral core particles. These initial studies, performed with E1E2 glycoproteins of genotype 1, noted that HCVpp closely mimic the cell entry and neutralization properties of parental HCV. Because sequence variations in E1 and E2 may account for differences in tropism, replication properties, neutralization, and response to treatment in patients infected with different genotypes, we investigated the functional properties of HCV envelope glycoproteins from different genotypes/subtypes. Our studies indicate that hepatocytes were preferential targets of infection in vitro, although HCV replication in extrahepatic sites has been reported in vivo. Receptor competition assays using antibodies against the CD81 ectodomain as well as ectopic expression of CD81 in CD81-deficient HepG2 cells indicated that CD81 is used by all the different genotypes/subtypes analyzed to enter the cells. However, by silencing RNA (siRNA) interference assays, our results show that the level of Scavenger Receptor Class-B Type-I (SR-BI) needed for efficient infection varies between genotypes and subtypes. Finally, sera from chronic HCV carriers were found to exhibit broadly reactive activities that inhibited HCVpp cell entry, but failed to neutralize all the different genotypes. In conclusion, we characterize common steps in the cell entry pathways of the major HCV genotypes that should provide clues for the development of cell entry inhibitors and vaccines. (HEPATOLOGY 2005;41:265,274.) [source]

Current therapy of HIV

JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, Issue 1 2010
Anja Verena Potthoff
Summary Antiretroviral therapy has improved continuously. Almost every year a new drug has been approved. Nucleoside analogs still build the backbone of antiretroviral therapy. They inhibit reverse transcriptase and thus the transcription of RNA to DNA. They are combined with non-nucleoside reverse transcriptase inhibitors or protease inhibitors. New therapeutic approaches are attachment or entry inhibitors, integrase inhibitors and maturation inhibitors. Multiple prospective multicenter studies have proven the life prolonging effect of antiretroviral therapy. With the optimal therapy life expectancy of HIV patients is only slightly reduced, similar to that of those with chronic diseases such as diabetes mellitus. One result of the higher age of HIV patients is an increase in concomitant diseases and medications. Drug interactions have to be considered and avoided. There has been a long discussion about the best time point to start antiretroviral therapy. In the late 1990s, every infected patient was treated hoping to eliminate the virus, ignoring the CD4+ cell count and viral load. This caused multiple (long-term) side effects and a rising resistance problem. The guidelines now recommend starting therapy at about 350/,l CD4 lymphocytes. Due to its complexity antiretroviral therapy should be initiated and monitored in specialized centers. [source]

Fusion core structure of the severe acute respiratory syndrome coronavirus (SARS-CoV): In search of potent SARS-CoV entry inhibitors

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2008
Ling-Hon Matthew Chu
Abstract Severe acute respiratory coronavirus (SARS-CoV) spike (S) glycoprotein fusion core consists of a six-helix bundle with the three C-terminal heptad repeat (HR2) helices packed against a central coiled-coil of the other three N-terminal heptad repeat (HR1) helices. Each of the three peripheral HR2 helices shows prominent contacts with the hydrophobic surface of the central HR1 coiled-coil. The concerted protein,protein interactions among the HR helices are responsible for the fusion event that leads to the release of the SARS-CoV nucleocapsid into the target host-cell. In this investigation, we applied recombinant protein and synthetic peptide-based biophysical assays to characterize the biological activities of the HR helices. In a parallel experiment, we employed a HIV-luc/SARS pseudotyped virus entry inhibition assay to screen for potent inhibitory activities on HR peptides derived from the SARS-CoV S protein HR regions and a series of other small-molecule drugs. Three HR peptides and five small-molecule drugs were identified as potential inhibitors. ADS-J1, which has been used to interfere with the fusogenesis of HIV-1 onto CD4+ cells, demonstrated the highest HIV-luc/SARS pseudotyped virus-entry inhibition activity among the other small-molecule drugs. Molecular modeling analysis suggested that ADS-J1 may bind to the deep pocket of the hydrophobic groove on the surface of the central coiled-coil of SARS-CoV S HR protein and prevent the entrance of the SARS-CoV into the host cells. J. Cell. Biochem. 104: 2335,2347, 2008. © 2008 Wiley-Liss, Inc. [source]