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10.1021/jacs.0c06400 http://scihub22266oqcxt.onion/10.1021/jacs.0c06400 32926779!7523239!32926779     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       J+Am+Chem+Soc 2020 ; 142 (40): 17024-17038 Nephropedia Template TP {{tp|p=32926779|t=2020. Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers |pdf=|usr=}}{{32926779}} gab.com Text Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers JO: J Am Chem Soc http://www.kidney.de/pget.php?&tw=1&pmid=32926779 #FOAvip 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. Twit Text FOAVip Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers ????J Am Chem Soc http://www.kidney.de/pget.php?&tw=1&pmid=32926779 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=32926779 #FOAvip English Wikipedia <ref>{{Cite pmid|32926779}}</ref> Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers #MMPMID32926779 Weil T; Gross R; Rocker A; Bravo-Rodriguez K; Heid C; Sowislok A; Le MH; Erwin N; Dwivedi M; Bart SM; Bates P; Wettstein L; Muller JA; Harms M; Sparrer K; Ruiz-Blanco YB; Sturzel CM; von Einem J; Lippold S; Read C; Walther P; Hebel M; Kreppel F; Klarner FG; Bitan G; Ehrmann M; Weil T; Winter R; Schrader T; Shorter J; Sanchez-Garcia E; Munch J J Am Chem Soc 2020[Oct]; 142 (40): 17024-17038 PMID32926779show ga 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. |Acid Phosphatase/chemistry/metabolism[MESH] |Amyloid/antagonists & inhibitors[MESH] |Anti-HIV Agents/chemistry/pharmacology[MESH] |Antiviral Agents/*chemistry/*pharmacology[MESH] |Arginine/chemistry[MESH] |Betacoronavirus/drug effects[MESH] |Bridged-Ring Compounds/chemistry/*pharmacology[MESH] |Cell Membrane/chemistry/drug effects/virology[MESH] |HIV Infections/drug therapy[MESH] |HIV-1/drug effects[MESH] |Humans[MESH] |Lipids/chemistry[MESH] |Lysine/chemistry[MESH] |Magnetic Resonance Spectroscopy[MESH] |Organophosphates/chemistry/*pharmacology[MESH] |SARS-CoV-2[MESH] |Seminal Vesicle Secretory Proteins/chemistry/metabolism[MESH] |Structure-Activity Relationship[MESH] |Viral Envelope Proteins/*drug effects/metabolism[MESH]Supramolecular Mechanism of Viral Envelope Disruption by Molecular Twe(epmc).pdf DeepDyve Pubget Overpricing