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1.
Molecules ; 26(20)2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1480883

ABSTRACT

Viral infections are among the most complex medical problems and have been a major threat to the economy and global health. Several epidemics and pandemics have occurred due to viruses, which has led to a significant increase in mortality and morbidity rates. Natural products have always been an inspiration and source for new drug development because of their various uses. Among all-natural sources, plant sources are the most dominant for the discovery of new therapeutic agents due to their chemical and structural diversity. Despite the traditional use and potential source for drug development, natural products have gained little attention from large pharmaceutical industries. Several plant extracts and isolated compounds have been extensively studied and explored for antiviral properties against different strains of viruses. In this review, we have compiled antiviral plant extracts and natural products isolated from plants reported since 2015.


Subject(s)
Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Biological Products/pharmacology , Drug Development , Plant Extracts/pharmacology , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/isolation & purification , Anti-HIV Agents/pharmacology , Antiviral Agents/chemistry , Biological Products/chemistry , Biological Products/isolation & purification , Drug Discovery , Flavivirus/drug effects , Hepatitis Viruses/drug effects , Humans , Molecular Structure , Orthomyxoviridae/drug effects , Plant Extracts/chemistry , Simplexvirus/drug effects
2.
Viruses ; 13(8)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1376995

ABSTRACT

In 2021, we commemorate the 40th anniversary of the identification of the disease AIDS, the acquired immune deficiency syndrome, a name that for the first time in history was launched in 1981 [...].


Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Anti-HIV Agents/history , Drug Discovery/history , HIV/drug effects , Suramin/history , Acquired Immunodeficiency Syndrome/history , Acquired Immunodeficiency Syndrome/virology , Anti-HIV Agents/chemistry , Anti-HIV Agents/therapeutic use , HIV/genetics , HIV/physiology , History, 20th Century , History, 21st Century , Humans , Suramin/chemistry , Suramin/therapeutic use
3.
Bioconjug Chem ; 32(6): 1067-1077, 2021 06 16.
Article in English | MEDLINE | ID: covidwho-1241779

ABSTRACT

Passing through the blood-brain barrier (BBB) to treat neurological conditions is one of the main hurdles in modern medicine. Many drugs with promising in vitro profiles become ineffective in vivo due to BBB restrictive permeability. In particular, this includes drugs such as antiviral porphyrins, with the ability to fight brain-resident viruses causing diseases such as HIV-associated neurocognitive disorders (HAND). In the last two decades, BBB shuttles, particularly peptide-based ones, have shown promise in carrying various payloads across the BBB. Thus, peptide-drug conjugates (PDCs) formed by covalent attachment of a BBB peptide shuttle and an antiviral drug may become key therapeutic tools in treating neurological disorders of viral origin. In this study, we have used various approaches (guanidinium, phosphonium, and carbodiimide-based couplings) for on-resin synthesis of new peptide-porphyrin conjugates (PPCs) with BBB-crossing and potential antiviral activity. After careful fine-tuning of the synthetic chemistry, DIC/oxyma has emerged as a preferred method, by which 14 different PPCs have been made and satisfactorily characterized. The PPCs are prepared by coupling a porphyrin carboxyl group to an amino group (either N-terminal or a Lys side chain) of the peptide shuttle and show effective in vitro BBB translocation ability, low cytotoxicity toward mouse brain endothelial cells, and low hemolytic activity. Three of the PPCs, MP-P5, P4-MP, and P4-L-MP, effectively inhibiting HIV infectivity in vitro, stand out as most promising. Their efficacy against other brain-targeting viruses (Dengue, Zika, and SARS-CoV-2) is currently under evaluation, with preliminary results confirming that PPCs are a promising strategy to treat viral brain infections.


Subject(s)
Anti-HIV Agents/pharmacokinetics , Blood-Brain Barrier/metabolism , Peptides/pharmacokinetics , Porphyrins/pharmacokinetics , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Biological Transport , Cell Line , Drug Discovery , HEK293 Cells , HIV/drug effects , HIV Infections/drug therapy , Humans , Mice , Peptides/chemistry , Peptides/pharmacology , Porphyrins/chemistry , Porphyrins/pharmacology
4.
J Am Chem Soc ; 142(40): 17024-17038, 2020 10 07.
Article in English | MEDLINE | ID: covidwho-772998

ABSTRACT

Broad-spectrum antivirals are powerful weapons against dangerous viruses where no specific therapy exists, as in the case of the ongoing SARS-CoV-2 pandemic. We discovered that a lysine- and arginine-specific supramolecular ligand (CLR01) destroys enveloped viruses, including HIV, Ebola, and Zika virus, and remodels amyloid fibrils in semen that promote viral infection. Yet, it is unknown how CLR01 exerts these two distinct therapeutic activities. Here, we delineate a novel mechanism of antiviral activity by studying the activity of tweezer variants: the "phosphate tweezer" CLR01, a "carboxylate tweezer" CLR05, and a "phosphate clip" PC. Lysine complexation inside the tweezer cavity is needed to antagonize amyloidogenesis and is only achieved by CLR01. Importantly, CLR01 and CLR05 but not PC form closed inclusion complexes with lipid head groups of viral membranes, thereby altering lipid orientation and increasing surface tension. This process disrupts viral envelopes and diminishes infectivity but leaves cellular membranes intact. Consequently, CLR01 and CLR05 display broad antiviral activity against all enveloped viruses tested, including herpesviruses, Measles virus, influenza, and SARS-CoV-2. Based on our mechanistic insights, we potentiated the antiviral, membrane-disrupting activity of CLR01 by introducing aliphatic ester arms into each phosphate group to act as lipid anchors that promote membrane targeting. The most potent ester modifications harbored unbranched C4 units, which engendered tweezers that were approximately one order of magnitude more effective than CLR01 and nontoxic. Thus, we establish the mechanistic basis of viral envelope disruption by specific tweezers and establish a new class of potential broad-spectrum antivirals with enhanced activity.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Bridged-Ring Compounds/pharmacology , Organophosphates/pharmacology , Viral Envelope Proteins/drug effects , Acid Phosphatase/chemistry , Acid Phosphatase/metabolism , Amyloid/antagonists & inhibitors , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Arginine/chemistry , Betacoronavirus/drug effects , Bridged-Ring Compounds/chemistry , Cell Membrane/chemistry , Cell Membrane/drug effects , Cell Membrane/virology , HIV Infections/drug therapy , HIV-1/drug effects , Humans , Lipids/chemistry , Lysine/chemistry , Magnetic Resonance Spectroscopy , Organophosphates/chemistry , SARS-CoV-2 , Seminal Vesicle Secretory Proteins/chemistry , Seminal Vesicle Secretory Proteins/metabolism , Structure-Activity Relationship , Viral Envelope Proteins/metabolism , Zika Virus/drug effects
5.
J Med Virol ; 92(10): 2087-2095, 2020 10.
Article in English | MEDLINE | ID: covidwho-763177

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) is the causative agent of the coronavirus disease-2019 (COVID-19) pandemic. Coronaviruses enter cells via fusion of the viral envelope with the plasma membrane and/or via fusion of the viral envelope with endosomal membranes after virion endocytosis. The spike (S) glycoprotein is a major determinant of virus infectivity. Herein, we show that the transient expression of the SARS CoV-2 S glycoprotein in Vero cells caused extensive cell fusion (formation of syncytia) in comparison to limited cell fusion caused by the SARS S glycoprotein. Both S glycoproteins were detected intracellularly and on transfected Vero cell surfaces. These results are in agreement with published pathology observations of extensive syncytia formation in lung tissues of patients with COVID-19. These results suggest that SARS CoV-2 is able to spread from cell-to-cell much more efficiently than SARS effectively avoiding extracellular neutralizing antibodies. A systematic screening of several drugs including cardiac glycosides and kinase inhibitors and inhibitors of human immunodeficiency virus (HIV) entry revealed that only the FDA-approved HIV protease inhibitor, nelfinavir mesylate (Viracept) drastically inhibited S-n- and S-o-mediated cell fusion with complete inhibition at a 10-µM concentration. 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 may act to inhibit S proteolytic processing within cells. These results warrant further investigations of the potential of nelfinavir mesylate to inhibit virus spread at early times after SARS CoV-2 symptoms appear.


Subject(s)
Anti-HIV Agents/pharmacology , Membrane Fusion/drug effects , Nelfinavir/pharmacology , SARS Virus/drug effects , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Animals , Anti-HIV Agents/chemistry , Binding Sites , COVID-19/drug therapy , Cell Fusion , Chlorocebus aethiops , Giant Cells/drug effects , Giant Cells/pathology , Giant Cells/virology , Humans , Molecular Docking Simulation , Nelfinavir/chemistry , Plasmids/chemistry , Plasmids/metabolism , Protein Binding , Protein Interaction Domains and Motifs , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , SARS Virus/pathogenicity , SARS Virus/physiology , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Virion/drug effects , Virion/pathogenicity , Virion/physiology
6.
Molecules ; 25(10)2020 May 17.
Article in English | MEDLINE | ID: covidwho-276849

ABSTRACT

Remdesivir is a nucleotide prodrug that is currently undergoing extensive clinical trials for the treatment of COVID-19. The prodrug is metabolized to its active triphosphate form and interferes with the action of RNA-dependent RNA polymerase of SARS-COV-2. Herein, we report the antiviral activity of remdesivir against human coronavirus 229E (HCoV-229E) compared to known anti-HIV agents. These agents included tenofovir (TFV), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC), known as nucleoside reverse-transcriptase inhibitors (NRTIs), and a number of 5'-O-fatty acylated anti-HIV nucleoside conjugates. The anti-HIV nucleosides interfere with HIV RNA-dependent DNA polymerase and/or act as chain terminators. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. The study revealed that remdesivir exhibited an EC50 value of 0.07 µM against HCoV-229E with TC50 of > 2.00 µM against MRC-5 cells. Parent NRTIs were found to be inactive against (HCoV-229E) at tested concentrations. Among all the NRTIs and 5'-O-fatty acyl conjugates of NRTIs, 5'-O-tetradecanoyl ester conjugate of FTC showed modest activity with EC50 and TC50 values of 72.8 µM and 87.5 µM, respectively. These data can be used for the design of potential compounds against other coronaviruses.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Anti-HIV Agents/pharmacology , Coronavirus 229E, Human/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , Anti-HIV Agents/chemistry , Betacoronavirus/drug effects , Betacoronavirus/enzymology , COVID-19 , Cell Line , Coronavirus 229E, Human/enzymology , Coronavirus Infections/drug therapy , Humans , Pandemics , Pneumonia, Viral/drug therapy , RNA-Dependent RNA Polymerase/metabolism , Reverse Transcriptase Inhibitors/chemistry , SARS-CoV-2
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