scholarly journals The anti‐HIV drug nelfinavir mesylate (Viracept) is a potent inhibitor of cell fusion caused by the SARSCoV‐2 spike (S) glycoprotein warranting further evaluation as an antiviral against COVID‐19 infections

2020 ◽  
Vol 92 (10) ◽  
pp. 2087-2095 ◽  
Author(s):  
Farhana Musarrat ◽  
Vladimir Chouljenko ◽  
Achyut Dahal ◽  
Rafiq Nabi ◽  
Tamara Chouljenko ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Potent Inhibitor ◽  
Nelfinavir Mesylate ◽  
Anti Hiv

scholarly journals The anti-HIV Drug Nelfinavir Mesylate (Viracept) is a Potent Inhibitor of Cell Fusion Caused by the SARS-CoV-2 Spike (S) Glycoprotein Warranting further Evaluation as an Antiviral against COVID-19 infections

2020 ◽  
Author(s):  
Farhana Musarrat ◽  
Vladimir Chouljenko ◽  
Rafiq Nabi ◽  
Achyut Dahal ◽  
Seetharama D. Jois ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Neutralizing Antibodies ◽  
Antiviral Drug ◽  
Proteolytic Processing ◽  
Viral Envelope ◽  
Hiv Protease ◽  
Virus Infectivity ◽  
Dependent Manner ◽  
African Green Monkey Kidney ◽  
Nelfinavir Mesylate

AbstractCoronaviruses belong to a group of enveloped, positive-single stranded RNA viruses that are known to cause severe respiratory distress in animals and humans. The current SARS coronavirus-2 (SARS CoV-2) pandemic has caused more than 2,000,000 infections globally and nearly 200,000 deaths. Coronaviruses enter susceptible cells via fusion of the viral envelope with the plasma membrane and/or via fusion of the viral envelope with endosomal membranes after endocytosis of the virus into endosomes. Previous results with SARS and MERS CoV have shown that the Spike (S) glycoprotein is a major determinant of virus infectivity and immunogenicity. Herein, we show that expression of SARS CoV-2 S (S-n) glycoprotein after transient transfection of African green monkey kidney (Vero) cells caused extensive cell fusion in comparison to limited cell fusion caused by the SARS S (S-o) glycoprotein. S-n expression was detected intracellularly and on transfected Vero cell surfaces and caused the formation of very large multinucleated cells (syncytia) by 48 hours post transfection. These results are in agreement with published pathology observations of extensive syncytial formation in lung tissues of COVID-19 patients. This differential S-n versus S-o-mediated cell fusion suggests that SARS-CoV-2 is able to spread from cell-to-cell much more efficiently than SARS effectively avoiding extracellular spaces and neutralizing antibodies. A systematic screening of several drugs for ability to inhibit S-n and S-o cell fusion revealed that the FDA approved HIV-protease inhibitor, nelfinavir mesylate (Viracept) drastically inhibited S-n and S-o-mediated cell fusion in a dose-dependent manner. Complete inhibition of cell fusion was observed at a 10 micromolar concentration. Computational modeling and in silico docking experiments suggested the possibility that nelfinavir may bind inside the S trimer structure, proximal to the S2 amino terminus directly inhibiting S-n and S-o-mediated membrane fusion. Also, it is possible that nelfinavir mesylate acts on cellular processes to inhibit S proteolytic processing. These results warrant further investigations of the potential of nelfinavir mesylate as an antiviral drug, especially at early times after SARS-CoV-2 symptoms appear.

Downsizing of an HIV–cell fusion inhibitor, T22 ([Tyr 5, 12 , Lys 7 ]-Polyphemusin II), with the maintenance of anti-HIV activity and solution structure 1

1998 ◽  
Vol 6 (4) ◽  
pp. 473-479 ◽  
Author(s):  
Hirokazu Tamamura ◽  
Michinori Waki ◽  
Makoto Imai ◽  
Akira Otaka ◽  
Toshiro Ibuka ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Solution Structure ◽  
Fusion Inhibitor ◽  
Anti Hiv

A Synthetic Peptide from HIV-1 gp41 Is a Potent Inhibitor of Virus-Mediated Cell—Cell Fusion

1993 ◽  
Vol 9 (11) ◽  
pp. 1051-1053 ◽  
Author(s):  
Carl Wild ◽  
Teresa Greenwell ◽  
Thomas Matthews
Keyword(s):  
Cell Fusion ◽  
Synthetic Peptide ◽  
Potent Inhibitor ◽  
Hiv 1 ◽  
Cell Cell

Synthesis, Biophysical Characterization, and Anti–HIV-1 Fusion Activity of DNA Quadruplex-based Inhibitors with Dipeptide MT Hook Conjugation

2021 ◽  
Vol 19 ◽  
Author(s):  
Liang Xu ◽  
Zeye Han ◽  
Hongqian Ren
Keyword(s):  
Cell Fusion ◽  
Envelope Glycoprotein ◽  
Heptad Repeat ◽  
Fusion Activity ◽  
Biophysical Characterization ◽  
G Quadruplex ◽  
Dna Quadruplex ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Cell Cell

Background: Human immunodeficiency virus type-1 (HIV-1) infection is the reason for the epidemic of acquired immunodeficiency syndrome (AIDS). Developing HIV-1 fusion inhibitors gained increasing attention as they took effect in the early stage of HIV-1 infecting cells. DNA G-quadruplex-based inhibitors had been found to interact with HIV-1 envelope glycoprotein, showing anti–HIV-1 fusion activity. C-peptide derived molecules with Met-Thr terminal also showed potent anti-fusion activity, the Met-Thr dipeptide adopted a hook-like structure (termed MT hook) in the hydrophobic pocket to "anchor" inhibitors to the N-terminal heptad repeat (NHR) of HIV-1 envelope glycoprotein gp41. Objective: Our work was to conjugate MT hooks to the 5'-terminal ends of DNA quadruplex-based inhibitor and demonstrate its biophysical characterization and anti–HIV-1 fusion activity. Methods: A 6-aminohexanol phosphonamidite was utilized in solid synthesis for the conjunction of oligodeoxynucleotide and MT dipeptide. Hydrophobic groups were introduced by a nucleoside analogue from the base site. Circular dichroism spectrum and native polyacrylamide gel electrophoresis were used to confirm the helix formation. A cell-cell fusion assay was carried out to test the anti-fusion activity. Results: The conjugate G1 showed improved anti-cell-cell fusion activity than quadruplex without MT hook. The MT hook did not affect the oligodeoxynucleotide (ODN) G-quadruplex assembly. It was also proved that G1 could effectively interfere with endogenous 6-helical bundle (6HB) formation between the N-terminal heptad repeat N36 (NHR) and the C-terminal heptad repeat C34 (CHR) during virus fusion course. Conclusion: In this work, conjugate of DNA-oligopeptide were successfully synthesized. The conjugation of MT hook did improve the anti-fusion activity of DNA G-quadruplex-based inhibitors. Our results can add information regarding on structure-activity relationships of DNA helix-based inhibitors and provide a reference for the follow-up experimental studies.

The Effect of Absolute Configuration on the Anti-HIV and Anti-HBV Activity of Nucleoside Analogues

1995 ◽  
Vol 6 (6) ◽  
pp. 345-355 ◽  
Author(s):  
P. A. Furman ◽  
J. E. Wilson ◽  
J. E. Reardon ◽  
G. R. Painter
Keyword(s):  
Dna Polymerase ◽  
Potent Inhibitor ◽  
Hbv Dna ◽  
The Other ◽  
Nucleoside Analogues ◽  
Differential Inhibition ◽  
Hiv Reverse Transcriptase ◽  
Hiv Rt ◽  
Anti Hiv ◽  
Selective Activity

This review concerns the effect of stereoisomerism on the selective activity of anti-HIV and anti-HBV nucleoside analogues. The synthesis of a number of nucleoside analogues with anti-HIV and anti-HBV activity yields mixtures of 1-β-D and 1-β-L stereoisomers. Anti-HIV and anti-HBV activity is associated primarily with one of the two enantiomers and the more potent activity does not always reside with the 1-β-D configuration characteristic of natural nucleosides. In the case of HIV, the origin of this stereoselectivity appears to be the result of differential metabolism of the analogues and not due to differential inhibition of the target enzyme; the HIV reverse transcriptase. However, mutations at position 184 of the HIV-RT does result in stereoselective inhibition of the enzyme. On the other hand, with HBV, there is also a stereoselective inhibition of the HBV DNA polymerase, where the 5′-triphosphate of the 1-β-L enantiomer is the more potent inhibitor.

scholarly journals Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89.

1997 ◽  
Vol 41 (5) ◽  
pp. 1099-1107 ◽  
Author(s):  
M B Faletto ◽  
W H Miller ◽  
E P Garvey ◽  
M H St Clair ◽  
S M Daluge ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Adenosine Deaminase ◽  
Mycophenolic Acid ◽  
Potent Inhibitor ◽  
Selective Inhibitor ◽  
Hiv Reverse Transcriptase ◽  
Adenylate Deaminase ◽  
Immunodeficiency Virus ◽  
Anti Hiv

The anabolism of 1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, a selective inhibitor of human immunodeficiency virus (HIV), was characterized in human T-lymphoblastoid CD4+ CEM cells. 1592U89 was ultimately anabolized to the triphosphate (TP) of the guanine analog (-)-carbovir (CBV), a potent inhibitor of HIV reverse transcriptase. However, less than 2% of intracellular 1592U89 was converted to CBV, an amount insufficient to account for the CBV-TP levels observed. 1592U89 was anabolized to its 5'-monophosphate (MP) by the recently characterized enzyme adenosine phosphotransferase, but neither its diphosphate (DP) nor its TP was detected. The MP, DP, and TP of CBV were found in cells incubated with either 1592U89 or CBV, with CBV-TP being the major phosphorylated species. We confirmed that CBV is phosphorylated by 5'-nucleotidase and that mycophenolic acid increased the formation of CBV-TP from CBV 75-fold. However, mycophenolic acid did not stimulate 1592U89 anabolism to CBV-TP. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) did not inhibit CBV-TP formation from CBV or 1592U89, whereas the adenylate deaminase inhibitor 2'-deoxycoformycin selectively inhibited 1592U89 anabolism to CBV-TP and reversed the antiviral activity of 1592U89. 1592U89-MP was not a substrate for adenylate deaminase but was a substrate for a distinct cytosolic deaminase that was inhibited by 2'-deoxycoformycin-5'-MP. Thus, 1592U89 is phosphorylated by adenosine phosphotransferase to 1592U89-MP, which is converted by a novel cytosolic enzyme to CBV-MP. CBV-MP is then further phosphorylated to CBV-TP by cellular kinases. This unique activation pathway enables 1592U89 to overcome the pharmacokinetic and toxicological deficiencies of CBV while maintaining potent and selective anti-HIV activity.

scholarly journals DNA Triplex-Based Complexes Display Anti-HIV-1-Cell Fusion Activity

2015 ◽  
Vol 25 (4) ◽  
pp. 219-225 ◽  
Author(s):  
Liang Xu ◽  
Tao Zhang ◽  
Xiaoyu Xu ◽  
Huihui Chong ◽  
Wenqing Lai ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Fusion Activity ◽  
Dna Triplex ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Potent Strategy To Inhibit HIV-1 by Binding both gp120 and gp41

2010 ◽  
Vol 55 (1) ◽  
pp. 264-275 ◽  
Author(s):  
Ioannis Kagiampakis ◽  
Arbi Gharibi ◽  
Marie K. Mankowski ◽  
Beth A. Snyder ◽  
Roger G. Ptak ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Hiv Replication ◽  
Nmr Spectrum ◽  
Binding Peptide ◽  
Hiv Entry ◽  
Covalently Linked ◽  
Hiv Gp120 ◽  
Hiv Microbicide ◽  
Anti Hiv ◽  
Cell Cell

ABSTRACTThe development of an anti-HIV microbicide is critical in the fight against the spread of HIV. It is shown here that the covalent linking of compounds that bind gp120 with compounds that bind gp41 can inhibit HIV entry even more potently than individual inhibitors or noncovalent combinations. The most striking example involves griffithsin, a potent HIV inhibitor that binds to the surface of HIV gp120. While griffithsin inhibits HIV Env-mediated fusion in a CCR5-tropic cell-cell fusion assay with a 50% inhibitory concentration (IC50) of 1.31 ± 0.87 nM and the gp41-binding peptide C37 shows an IC50of 18.2 ± 7.6 nM, the covalently linked combination of griffithsin with C37 (Griff37) has an IC50of 0.15 ± 0.05 nM, exhibiting a potency 8.7-fold greater than that of griffithsin alone. Similarly, in CXCR4-tropic cell-cell fusion assays, Griff37 is 5.2-fold more potent than griffithsin alone. In viral assays, both griffithsin and Griff37 inhibit HIV replication at midpicomolar levels, but the linked compound Griff37 is severalfold more potent than griffithsin alone against both CCR5- and CXCR4-tropic virus strains. Another example of this strategy is the covalently linked combination of peptide C37 with a variant of the gp120-binding peptide CD4M33 (L. Martin et al., Nat. Biotechnol. 21:71-76, 2003). Also, nuclear magnetic resonance (NMR) spectra for several of these compounds are shown, including, to our knowledge, the first published NMR spectrum for griffithsin.

scholarly journals Broadly Neutralizing Anti-HIV-1 Antibodies Do Not Inhibit HIV-1-ENV-Mediated Cell-Cell Fusion

2018 ◽  
Vol 114 (3) ◽  
pp. 603a-604a
Author(s):  
Nejat Duzgunes ◽  
Michael Yee ◽  
Deborah Chau
Keyword(s):  
Cell Fusion ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Cell Cell
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