scholarly journals Biological Evaluation of Molecules of the azaBINOL Class as Antiviral Agents: Specific Inhibition of HIV-1 RNase H Activity by 7-Isopropoxy-8-(naphth-1-yl)quinoline

2019 ◽  
Author(s):  
Ross D. Overacker ◽  
Somdev Banerjee ◽  
George F. Neuhaus ◽  
Selena Milicevic Sephton ◽  
Alexander Herrmann ◽  
...  
Keyword(s):  
Viral Entry ◽  
Antiviral Agents ◽  
Biological Evaluation ◽  
Rnase H ◽  
Synthetic Compounds ◽  
Infectivity Assay ◽  
Antiviral Compounds ◽  
Specific Manner ◽  
Drug Leads ◽  
Hiv 1

AbstractInspired by bioactive biaryl-containing natural products found in plants and the marine environment, a series of synthetic compounds belonging to the azaBINOL chiral ligand family was evaluated for antiviral activity against HIV-1. Testing of 39 unique azaBINOLs in a singleround infectivity assay resulted in the identification of three promising antiviral compounds, including 7-isopropoxy-8-(naphth-1-yl)quinoline (azaBINOLB#24), which exhibited low-micromolar activity. The active compounds and several close structural analogues were further tested against three different HIV-1 envelope pseudotyped viruses as well as in a full-virus replication system (EASY-HIT). Mode-of-action studies using a time-of-addition assay indicated that azaBINOLB#24acts after viral entry but before viral assembly and budding. HIV-1 reverse transcriptase (RT) assays that individually test for polymerase and RNase H activity were used to demonstrate thatB#24inhibits RNase H activity, most likely allosterically. Further binding analysis using bio-layer interferometry (BLI) showed thatB#24interacts with HIV-1 RT in a highly specific manner. These results indicate that azaBINOLB#24is a potentially viable, novel lead for the development of new HIV-1 RNase H inhibitors. Furthermore, this study demonstrates that the survey of libraries of synthetic compounds, designed purely with the goal of facilitating chemical synthesis in mind, may yield unexpected and selective drug leads for the development of new antiviral agents.

scholarly journals Biological evaluation of molecules of the azaBINOL class as antiviral agents: Inhibition of HIV-1 RNase H activity by 7-isopropoxy-8-(naphth-1-yl)quinoline

2019 ◽  
Vol 27 (16) ◽  
pp. 3595-3604 ◽  
Author(s):  
Ross D. Overacker ◽  
Somdev Banerjee ◽  
George F. Neuhaus ◽  
Selena Milicevic Sephton ◽  
Alexander Herrmann ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Biological Evaluation ◽  
Rnase H ◽  
Hiv 1

The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review

2019 ◽  
Vol 19 (18) ◽  
pp. 1650-1675 ◽  
Author(s):  
Damoder Reddy Motati ◽  
Dilipkumar Uredi ◽  
E. Blake Watkins
Keyword(s):  
Small Molecule ◽  
Viral Entry ◽  
Biological Evaluation ◽  
New Drugs ◽  
Design Synthesis ◽  
Mortality And Morbidity ◽  
Glycoprotein Gp120 ◽  
Hiv Entry ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.

scholarly journals The Combined Use of Alphavirus Replicons and Pseudoinfectious Particles for the Discovery of Antivirals Derived from Natural Products

2014 ◽  
Vol 20 (5) ◽  
pp. 673-680 ◽  
Author(s):  
Phillip C. Delekta ◽  
Avi Raveh ◽  
Martha J. Larsen ◽  
Pamela J. Schultz ◽  
Giselle Tamayo-Castillo ◽  
...  
Keyword(s):  
Life Cycle ◽  
Antiviral Activity ◽  
Viral Entry ◽  
Particle System ◽  
Antiviral Agents ◽  
Viral Life Cycle ◽  
Genome Replication ◽  
Bacterial Strains ◽  
Antiviral Compounds ◽  
Western Equine Encephalitis

Alphaviruses are a prominent class of reemergent pathogens due to their globally expanding ranges, potential for lethality, and possible use as bioweapons. The absence of effective treatments for alphaviruses highlights the need for innovative strategies to identify antiviral agents. Primary screens that use noninfectious self-replicating RNAs, termed replicons, have been used to identify potential antiviral compounds for alphaviruses. Only inhibitors of viral genome replication, however, will be identified using replicons, which excludes many other druggable steps in the viral life cycle. To address this limitation, we developed a western equine encephalitis virus pseudoinfectious particle system that reproduces several crucial viral life cycle steps in addition to genome replication. We used this system to screen a library containing ~26,000 extracts derived from marine microbes, and we identified multiple bacterial strains that produce compounds with potential antiviral activity. We subsequently used pseudoinfectious particle and replicon assays in parallel to counterscreen candidate extracts, and followed antiviral activity during biochemical fractionation and purification to differentiate between inhibitors of viral entry and genome replication. This novel process led to the isolation of a known alphavirus entry inhibitor, bafilomycin, thereby validating the approach for the screening and identification of potential antiviral compounds.

scholarly journals Recent Advances in Tetrazole Derivatives as Potential Antiviral Agents

2021 ◽  
Vol 33 (11) ◽  
pp. 2599-2607
Author(s):  
Ruchika Yogesh ◽  
Noopur Srivastava
Keyword(s):  
Antiviral Agents ◽  
Acid Amide ◽  
Host Cells ◽  
Carboxylic Acid Amide ◽  
Synthetic Compounds ◽  
Scientific Databases ◽  
The Past ◽  
Antiviral Compounds ◽  
Pharmaceutical Agents ◽  
Tetrazole Derivatives

Viruses use the host cell’s biochemical machinery for replication and survival; and also undergo mutations to evade the immune response and achieve better transmission. These features make it challenging to develop selective drugs to kill viruses only and not the host cells. New and effective pharmaceutical agents are required to overcome this challenge. Tetrazole moiety, as a bio-isostere of carboxylic acid/amide group, has been extensively used as a potent pharmacophore in several bioactivities. Intrigued by the necessity of finding new antiviral compounds and tendency of tetrazole scaffolds to render various bioactivity profiles, this review article comprising literature reports of tetrazole-based synthetic compounds with promising antiviral activity is presented. This review comprises significant literature reports from the scientific databases published during the past four decades. It is found that tetrazole based molecules are promising endeavor for the development of potential agents against influenza virus, HIV, HCV and other viruses.

scholarly journals Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: Synthesis and Biological Evaluation of Novel Quinoxalinylethylpyridylthioureas as Potent Antiviral Agents

2000 ◽  
Vol 11 (2) ◽  
pp. 141-155 ◽  
Author(s):  
G Campiani ◽  
M Fabbrini ◽  
E Morelli ◽  
V Nacci ◽  
G Greco ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Antiviral Agents ◽  
Human Monocyte ◽  
Biological Evaluation ◽  
Single Amino Acid ◽  
Enzymatic Assays ◽  
Immunodeficiency Virus ◽  
Heterocyclic Derivatives ◽  
Rt Inhibitors ◽  
Hiv 1

New heterocyclic derivatives of ethylpyridylthiourea, quinoxalinylethylpyridylthiourea (QXPT) and analogues, inhibited human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevented HIV-1 cytopathogenicity in T4 lymphocytes. Several of these novel non-nucleoside RT inhibitors, with a substituted pyrroloquinoxalinone heteroaromatic skeleton, showed inhibitory activity against wild-type RT as well as against mutant RTs containing the single amino acid substitutions L100I, K103N, V106A, Y181I and Y188L that was much greater than other non-nucleoside inhibitors such as nevirapine. Maximum potency in enzymatic assays was achieved with a fluoropyrroloquinoxaline skeleton linked to the ethylpyridylthiourea moiety (FQXPT). In cell-based assays on different cell lines and on human monocyte-macrophages, 6-FQXPT exhibited EC50 values in the nanomolar range, with a promising selectivity index. Moreover, 6-FQXPT showed synergistic antiviral activity with zidovudine.

scholarly journals gp120 Alters Its Conformation to Enhance Evasiveness and Infectivity

2021 ◽  
Author(s):  
Joseph A. Ayariga ◽  
Logan Gildea ◽  
Ayodeji Ipimoroti ◽  
Qiana L. Matthews
Keyword(s):  
Structural Dynamics ◽  
Viral Entry ◽  
Antiviral Agents ◽  
Host Immunity ◽  
Viral Envelope ◽  
Cell Surface Receptor ◽  
Type I ◽  
Structural Constraints ◽  
Conformational States ◽  
Hiv 1

Infection by human immunodeficiency virus type I (HIV-1) requires virus particle binding to host cell-surface receptor CD4 via the viral envelope glycoprotein gp120. HIV-1 therapy and prevention efforts involve development of mimetic or recombinant gp120 vaccines or deployment of antiviral agents that target specific epitopes of gp120. The unliganded conformational state of gp120 is closed, whereas the CD4-bound state is open. However, in between, there exist dynamic conformational states, indicating intrinsically flexible region(s) of structural dynamics, imposing a structural challenge for developing drug or antibody targets. Known conformational states of gp120 were determined by X-ray crystallographic and cryo-electron microscopy, and neither method captures the population of gp120 species arising from conformational plasticity, motions, and transitions. gp120 plasticity brings up several important questions. How will differences in conformation affect receptor binding, antibody recognition, and neutralization? Which regions are crucial for gp120 structural plasticity? How could structural dynamics influence HIV-1 evasiveness against host immunity and drugs or vaccines, and facilitate the viral entry into its host? This review explores the structural constraints presented by conformational states of the glycoprotein to antibodies or drugs and how these conformational states provide structural avenues for the virus to escape neutralizing agents and evade host immunity.

scholarly journals Chemical Characterization and Anti-HIV-1 Activity Assessment of Iridoids and Flavonols from Scrophularia trifoliata

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4777
Author(s):  
Francesca Guzzo ◽  
Rosita Russo ◽  
Cinzia Sanna ◽  
Odeta Celaj ◽  
Alessia Caredda ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Wide Spectrum ◽  
Iridoid Glycosides ◽  
Antiviral Agents ◽  
Chemical Characterization ◽  
Biological Properties ◽  
Rnase H ◽  
Chemical Structures ◽  
First Time ◽  
Hiv 1

Plants are the everlasting source of a wide spectrum of specialized metabolites, characterized by wide variability in term of chemical structures and different biological properties such antiviral activity. In the search for novel antiviral agents against Human Immunodeficiency Virus type 1 (HIV-1) from plants, the phytochemical investigation of Scrophularia trifoliata L. led us to isolate and characterize four flavonols glycosides along with nine iridoid glycosides, two of them, 5 and 13, described for the first time. In the present study, we investigated, for the first time, the contents of a methanol extract of S. trifoliata leaves, in order to explore the potential antiviral activity against HIV-1. The antiviral activity was evaluated in biochemical assays for the inhibition of HIV-1Reverse Transcriptase (RT)-associated Ribonuclease H (RNase H) activity and HIV-1 Integrase (IN). Three isolated flavonoids, rutin, kaempferol-7-O-rhamnosyl-3-O-glucopyranoside, and kaempferol-3-O-glucopyranoside, 8–10, inhibited specifically the HIV-1 IN activity at submicromolar concentration, with the latter being the most potent, showing an IC50 value of 24 nM.

scholarly journals Rapid Prescreening for Antiviral Agents against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. II. Porphyrins Reacting with the V3 Loop of gp120

1992 ◽  
Vol 3 (1) ◽  
pp. 55-63 ◽  
Author(s):  
A. R. Neurath ◽  
N. Strick ◽  
P. Haberfield ◽  
S. Jiang
Keyword(s):  
Antiviral Activity ◽  
Inhibitory Activity ◽  
Antiviral Agents ◽  
V3 Loop ◽  
Antiviral Compounds ◽  
Porphyrin Derivatives ◽  
Immunodeficiency Virus ◽  
Glycoprotein Gp120 ◽  
The Relationship ◽  
Hiv 1

Recent observations that haernin inhibited the replication of the human immunodeficiency virus (HIV-1) and the reaction between the HIV-1 envelope glycoprotein gp120 and antibodies specific for the V3 hypervariable loop of this glycoprotein were an enticement to determine whether or not additional porphyrins had similar activities. Several porphyrin derivatives, particularly meso-tetra (4-carboxyphenyl) porphine, were more potent inhibitors of HIV-1 replication than haernin. They blocked the binding of homologous antibodies to synthetic peptides corresponding to V3 hypervariable loops of 21 distinct HIV-1 isolates, and inhibited the replication in lymphocytic (MT-2) and promonocyte (U937) cell lines of several HIV-1 isolates, tested (IIIB, RF, SF-2, and MN). Compounds with inhibitory activity had a tetrapyrrole ring and, carboxyl or sulphonate groups. However, antiviral activity depended on minor structural difference's between distinct derivatives endowed with these two features. Metalloporphyrins had a drastically reduced antiviral activity in comparison with the corresponding porphyrins. An understanding of the relationship between the structure of porphyrins and their antiviral effects, perceptible from the results presented, is expected to lead to the design of additional derivatives with more potent antiviral activity and to unravelling of molecular details involved in the association between the V3 loop of gp120 and antiviral compounds targeted to this loop.

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