Novel concepts for the treatment of HSV-2 and other enveloped viruses
Einem, Jens von
InstitutionsUKU. Institut für Molekulare Virologie
Kompetenzzentrum "Ulm Peptide Pharmaceuticals (U-PEP)"
UKU. Institut für Virologie
LicenseStandard (ohne Print-on-Demand)
Until now, there are many antiviral drugs on the market but only selected viruses are targeted. In many cases, drugs are often invented in the aftermath of an outbreak and only the symptoms are treated. To prevent epidemic outbreaks of viruses broad-spectrum antiviral agents are highly appealing. Macromolecular prodrugs consisting of polymeric anions were generated and studied to address these unmet medical needs. Poly(vinylbenzoic acid) (PVBzA), was the only compound that inhibited all tested enveloped viruses. PVBzA is a compound with an anionic as well as hydrophobic character. It was shown, that both characteristics are necessary to inhibit viruses. The proposed mode of action is the interaction with viral glycoprotein and an increased electrostatic repulsion and therefore inhibiting the viral attachment. This can be an attempt for the use as microbicide in antiviral gels, sprays, or coatings for diverse biomedical and biotechnological applications. Beyond a direct antiviral activity, macromolecular complexes are promising tools to optimize the delivery and to improve the pharmacokinetics of already existing drugs. Therefore, macromolecular prodrugs of acyclovir were developed. Acyclovir was conjugated via a self-immolative linker to a polymer to achieve high payload. The polymers linked to a fatty acid bind albumin and thereby increase the half-life of acyclovir, which is of special interest for injections. Those macromolecular prodrugs showed in vitro as well as in vivo efficacy by protecting mice from Herpes simplex virus type 2 (HSV-2) infections after subcutaneous administration prior to vaginal infection. Formulations, such as 1,2-distearoyl-sn-glycero-3-phosphoethanolamine poly(N-(2-hydroxypropyl)methacrylamide) acyclovir (DSPE-PHPMA-ACV) can non-covalently bind to albumin and can reduce the administration by prolonging the duration of the drugs. Another antiviral treatment approach were macromolecular prodrugs based on natural nucleic acid scaffolds. Nucleoside analogues, specifically idoxuridine and trifluridine were used to synthesize molecularly defined therapeutic nucleic acids (TNA). TNAs were efficiently taken up by cells, followed by nuclease-mediated degradation which releases the active monomers. Especially idoxuridine-containing TNAs showed antiviral activity against Herpes simplex virus type 1 (HSV-1) and HSV-2, with a superior potency compared to the parent drug. Therefore, TNAs appear to be of high interest due to their natural degradation, the controllable composition, which can also be used in combinatorial therapies and their superior potency. Altogether, macromolecular prodrugs might be tested as novel concepts to treat HSV-2 and other enveloped viruses and therefore represent interesting tools for antiviral therapies regarding their high payload, their modifiability e.g. for increasing the body half-life and their possibility to be used as broad-spectrum microbicides.
Subject HeadingsHerpes-simplex-Virus [GND]
Herpesvirus 2, Human [MeSH]
Zika virus infection [MeSH]
Herpesviridae infections [MeSH]
Nucleic acids; Therapeutic use [MeSH]