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1.
ACS Infect Dis ; 8(10): 2084-2095, 2022 Oct 14.
Article in English | MEDLINE | ID: covidwho-2076976

ABSTRACT

Viruses are microscopic pathogens capable of causing disease and are responsible for a range of human mortalities and morbidities worldwide. They can be rendered harmless or destroyed with a range of antiviral chemical compounds. Cucurbit[n]urils (CB[n]s) are a family of macrocycle chemical compounds existing as a range of homologues; due to their structure, they can bind to biological materials, acting as supramolecular "hosts" to "guests", such as amino acids. Due to the increasing need for a nontoxic antiviral compound, we investigated whether cucurbit[n]urils could act in an antiviral manner. We have found that certain cucurbit[n]uril homologues do indeed have an antiviral effect against a range of viruses, including herpes simplex virus 2 (HSV-2), respiratory syncytial virus (RSV) and SARS-CoV-2. In particular, we demonstrate that CB[7] is the active homologue of CB[n], having an antiviral effect against enveloped and nonenveloped species. High levels of efficacy were observed with 5 min contact times across different viruses. We also demonstrate that CB[7] acts with an extracellular virucidal mode of action via host-guest supramolecular interactions between viral surface proteins and the CB[n] cavity, rather than via cell internalization or a virustatic mechanism. This finding demonstrates that CB[7] acts as a supramolecular virucidal antiviral (a mechanism distinct from other current extracellular antivirals), demonstrating the potential of supramolecular interactions for future antiviral disinfectants.


Subject(s)
COVID-19 , Disinfectants , Macrocyclic Compounds , Amino Acids , Antiviral Agents/pharmacology , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , Humans , Imidazoles/chemistry , Macrocyclic Compounds/chemistry , Membrane Proteins , SARS-CoV-2
2.
PLoS One ; 16(9): e0251951, 2021.
Article in English | MEDLINE | ID: covidwho-1394538

ABSTRACT

The purpose of this study was to explore potential mechanisms of cytotoxicity towards HeLa and HT29 cells displayed by Pediocin PA-1. We did this by carrying out sequence alignments and 3D modelling of related bacteriocins which have been studied in greater detail: Microcin E492, Enterocin AB heterodimer and Divercin V41. Microcin E492 interacts with Toll-Like Receptor 4 in order to activate an apoptosis reaction, sequence alignment showed a high homology between Pediocin PA-1 and Microcin E492 whereas 3D modelling showed Pediocin PA-1 interacting with TLR-4 in a way reminiscent of Microcin E492. Furthermore, Pediocin PA-1 had the highest homology with the Enterocin heterodimer, particularly chain A; Enterocin has also shown to cause an apoptotic response in cancer cells. Based on this we are led to strongly believe Pediocin PA-1 interacts with TLRs in order to cause cell death. If this is the case, it would explain the difference in cytotoxicity towards HeLa over HT29 cells, due to difference in expression of particular TLRs. Overall, we believe Pediocin PA-1 exhibits a dual effect which is dose dependant, like that of Microcin. Unfortunately, due to the COVID-19 pandemic, we were unable to carry out experiments in the lab, and the unavailability of important data meant we were unable to provide and validate out solid conclusions, but rather suggestions. However, bioinformatic analysis is still able to provide information regarding structure and sequence analysis to draw plausible and evidence based conclusions. We have been able to highlight interesting findings and how these could be translated into future research and therapeutics in order to improve the quality of treatment and life of cancer patients.


Subject(s)
Bacteriocins/chemistry , Bacteriocins/pharmacology , Pediocins/chemistry , Pediocins/pharmacology , Protein Conformation , Amino Acid Sequence , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Apoptosis/drug effects , Bacteriocins/genetics , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , Cell Survival/drug effects , HT29 Cells , HeLa Cells , Humans , Models, Molecular , Pandemics , Pediocins/genetics , SARS-CoV-2/physiology , Sequence Homology, Amino Acid , Toll-Like Receptor 4/metabolism
3.
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
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