Inhibition of Herpes Simplex Virus Type 1 Attachment and Infection by Sulfated Polyglycerols with Different Architectures

Pouyan, Paria; Nie, Chuanxiong; Bhatia, Sumati; Wedepohl, Stefanie; Achazi, Katharina; Osterrieder, Nikolaus; Haag, Rainer

doi:10.1021/acs.biomac.0c01789

Cited by 32 publications

(53 citation statements)

References 47 publications

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“…Our group has developed several synthetic polyglycerol sulfates (LPGS and HPGS) as heparin‐mimetic polymers in the past years [32, 33] . With similar charge density, the polyglycerol sulfates exhibit lower anticoagulant activity than heparin [32] .…”

Section: Resultsmentioning

confidence: 99%

Polysulfates Block SARS‐CoV‐2 Uptake through Electrostatic Interactions**

et al. 2021

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Here we report that negatively charged polysulfates can bind to the spike protein of SARS‐CoV‐2 via electrostatic interactions. Using a plaque reduction assay, we compare inhibition of SARS‐CoV‐2 by heparin, pentosan sulfate, linear polyglycerol sulfate (LPGS) and hyperbranched polyglycerol sulfate (HPGS). Highly sulfated LPGS is the optimal inhibitor, with an IC50 of 67 μg mL−1 (approx. 1.6 μm). This synthetic polysulfate exhibits more than 60‐fold higher virus inhibitory activity than heparin (IC50: 4084 μg mL−1), along with much lower anticoagulant activity. Furthermore, in molecular dynamics simulations, we verified that LPGS can bind more strongly to the spike protein than heparin, and that LPGS can interact even more with the spike protein of the new N501Y and E484K variants. Our study demonstrates that the entry of SARS‐CoV‐2 into host cells can be blocked via electrostatic interactions, therefore LPGS can serve as a blueprint for the design of novel viral inhibitors of SARS‐CoV‐2.

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Section: Resultsmentioning

confidence: 99%

Polysulfates Block SARS‐CoV‐2 Uptake through Electrostatic Interactions**

et al. 2021

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“…In den vergangen Jahren haben wir mehrere synthetische Polyglycerolsulfate (LPGS und HPGS) als Heparin‐Mimetika entwickelt [32, 33] . Bei ähnlicher Ladungsdichte zeigen die Polyglycerolsulfate eine geringere gerinnungshemmende Aktivität als Heparin [32] .…”

Section: Ergebnisse Und Diskussionunclassified

“…HPGS hingegen hat eine eher starre, kugelförmige Struktur und kann seine Konformation wenig an die Bindungstasche anpassen. Ähnliche Ergebnisse wurden bei der Untersuchung von Influenza‐ und Herpes‐Simplex‐Virus‐Inhibitoren beobachtet, bei denen die linearen Konstrukte besser abschnitten als hyperverzweigte Konstrukte bei gleichem Molekulargewicht [32, 35] …”

Section: Ergebnisse Und Diskussionunclassified

“…In den vergangen Jahren haben wir mehrere synthetische Polyglycerolsulfate (LPGS und HPGS) als Heparin-Mimetika entwickelt. [32,33] Bei ähnlicher Ladungsdichte zeigen die Polyglycerolsulfate eine geringere gerinnungshemmende Aktivitäta ls Heparin. [32] Die Hemmaktivitätd ieser Polysulfate gegenüber SARS-CoV-2 wurde eingehend untersucht und mit der von Heparin verglichen, um einen Ansatzpunkt fürd as Design zukünftiger Inhibitoren zu erhalten.…”

Section: Ergebnisse Und Diskussionunclassified

“…¾hnliche Ergebnisse wurden bei der Untersuchung von Influenza-und Herpes-Simplex-Virus-Inhibitoren beobachtet, bei denen die linearen Konstrukte besser abschnitten als hyperverzweigte Konstrukte bei gleichem Molekulargewicht. [32,35] Ein Viruziditätsassay zeigte,d ass SARS-CoV-2 nicht irreversibel durch LPG 20 S 0.94 und Heparin gehemmt wurde (siehe auch Hintergrundinformationen Abbildung S5). Verdünnt man die Lçsung,l çsen sich die Virionen aus der Bindung,w as unsere Behauptung stützt, dass das LPG 20 S 0.94 SARS-CoV-2 durch elektrostatische Wechselwirkungen mit dem Spike-Protein hemmt.…”

Section: Ergebnisse Und Diskussionunclassified

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Polysulfate hemmen durch elektrostatische Wechselwirkungen die SARS‐CoV‐2‐Infektion**

et al. 2021

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Here we report that negatively charged polysulfates can bind to the spike protein of SARS-CoV-2 via electrostatic interactions. Using a plaque reduction assay, we compare inhibition of SARS-CoV-2 by heparin, pentosan sulfate, linear polyglycerol sulfate (LPGS) and hyperbranched polyglycerol sulfate (HPGS). Highly sulfated LPGS is the optimal inhibitor, with a half-maximal inhibitory concentration (IC50) of 67 μg/mL (approx. 1.6 μM). This synthetic polysulfates exhibit more than 60-fold higher virus inhibitory activity than heparin (IC50: 4084 μg/mL), along with much lower anticoagulant activity. Furthermore, in molecular dynamics simulations, we verified that LPGS can bind stronger to the spike protein than heparin, and that LPGS can interact even more with the spike protein of the new N501Y and E484K variants. Our study demonstrates that the entry of SARS-CoV-2 into host cells can be blocked via electrostatic interaction, therefore LPGS can serve as a blueprint for the design of novel viral inhibitors of SARS-CoV-2.supply of SARS-CoV-2 RBD from the lab of Dr. Coskun (TU Dresden), and ACE2 protein from Prof. Bader at MDC Berlin.

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Bioactive Synthetic Polymers

et al. 2021

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Progress in these arenas has been driven by the discovery of inert, biocompatible polymers to provide the desired function without eliciting undesirable responses from the host environment. While concerns regarding the fate of these materials have led to an ongoing hunt for bioresorbable materials, it is important to note that synthetic polymers have been reported to elicit a biological response on their own. [2j,5] While the biological response is often toxic in nature and therefore undesirable for many applications, it poses a question: can the intrinsic bioactivity of synthetic polymers be harnessed for therapeutic interventions? This idea of intrinsic bioactivity is distinct from the long history of work pertaining to the use of synthetic polymers within biomedical settings. Polymers have indeed been extensively explored and continue to be investigated as (nano)carriers facilitating the delivery of bioactive payloads; in the majority of cases, the (nano)carrier bereft of its cargo is presented to provide little to no effect, demonstrating its role as an ideal delivery vehicle. [6] Polymers with intrinsic bioactivity diverge from this well-known concept by inducing biological change (i.e., bioactivity) by themselves in the absence of any conjugated or encapsulated species. [7] Interestingly, this previously posed question generated significant interest prior to the advent of drug-delivery approaches. [8] Among these early studies, a synthetic polymer, designated DIVEMA, garnered significant attention for its presentation of an outstanding breadth of bioactivity. [9] DIVEMA is a copolymer of divinyl ether (DVE) and maleic anhydride (MA) in a 1:2 ratio, with its proposed cyclopolymerization mechanism affording an in-chain pyran which consequently caused it to be more prominently known as Pyran copolymer. A hydrolyzed and neutralized version received the designation NSC 46015 and was approved for experimental clinical evaluation due to its antitumor activity against several cancers, including Adenocarcinoma 755, Lewis lung carcinoma, and Dunning ascites leukemia. [10] Moreover, its ability to induce interferon expression led to its evaluation against several viruses and reports of prophylactic action in murine models. DIVEMA has also demon strated antimicrobial activity against both Grampositive and Gram-negative bacteria and fungi. Despite this wide-ranging bioactivity, DIVEMA also presented a number of toxic side effects, the summation of which was not favorable for clinical use. Such side effects were common to many of the investigated synthetic polymers of the time and their failure in clinical trials is reflected in an absence of such therapeutic interventions as approved medicines.Synthetic polymers are omnipresent in society as textiles and packaging materials, in construction and medicine, among many other important applications. Alternatively, natural polymers play a crucial role in sustaining life and allowing organisms to adapt to their environments by performing key biological functions such as m...

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Inhibition of Herpes Simplex Virus Type 1 Attachment and Infection by Sulfated Polyglycerols with Different Architectures

Cited by 32 publications

References 47 publications

Polysulfates Block SARS‐CoV‐2 Uptake through Electrostatic Interactions**

Polysulfates Block SARS‐CoV‐2 Uptake through Electrostatic Interactions**

Polysulfate hemmen durch elektrostatische Wechselwirkungen die SARS‐CoV‐2‐Infektion**

Bioactive Synthetic Polymers

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