ganciclovir and Virus-Diseases

The AAA+ ATPase, p97, also referred to as VCP, plays an essential role in cellular homeostasis by regulating endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation (MAD), chromatin-associated degradation, autophagy, and endosomal trafficking. Mutations in p97 have been linked to a number of neurodegenerative diseases, and overexpression of wild type p97 is observed in numerous cancers. Furthermore, p97 activity has been shown to be essential for the replication of certain viruses, including poliovirus, herpes simplex virus (HSV), cytomegalovirus (CMV), and influenza. Taken together, these observations highlight the potential for targeting p97 as a therapeutic approach in neurodegeneration, cancer, and certain infectious diseases. This Perspective reviews recent advances in the discovery of small molecule inhibitors of p97, their optimization and characterization, and therapeutic potential.

Topics: Acetanilides; Animals; Benzothiazoles; Drug Delivery Systems; Endoplasmic Reticulum; Humans; Neoplasms; Neurodegenerative Diseases; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Valosin Containing Protein; Virus Diseases

Series of novel acyclic nucleoside phosphonates (ANPs) with various nucleobases and 2-(2-phosphonoethoxy)ethyl (PEE) chain bearing various substituents in β-position to the phosphonate moiety were prepared. The influence of structural alternations on antiviral activity was studied. Several derivatives exhibit antiviral activity against HIV and vaccinia virus (middle micromolar range), HSV-1 and HSV-2 (lower micromolar range) and VZV and CMV (nanomolar range), although the parent unbranched PEE-ANPs are inactive. Adenine as a nucleobase and the methyl group attached to the PEE chain proved to be a prerequisite to afford pronounced antiviral activity.

Topics: Animals; Antiviral Agents; Cell Line; Cell Survival; Herpes Simplex; HIV; HIV Infections; Humans; Mice; Nucleosides; Organophosphonates; Simplexvirus; Structure-Activity Relationship; Vaccinia; Vaccinia virus; Virus Diseases; Viruses

A series of aryl bis(3'-O-acetylthymidin-5'-yl) phosphate derivatives have been synthesized in order to find a suitable aryl derivative which would hydrolyze to the bis(nucleosid-5'-yl) phosphate under physiological conditions. The 4-(methylsulfonyl)phenyl derivative was selected and 4-(methylsulfonyl)phenyl bis[(E)-5-(2-bromovinyl)-2'-deoxyuridin-5'-yl] phosphate (6d) and bis[2-(guanin-9-ylmethoxy)ethoxy]-4-(methylsulfonyl)phenyl phosphate (7b) were prepared. The former compound (6d) was stable in human serum and only following hydrolysis to the 5'-5'-linked diester (half-life of 17 h at pH 7.7) was it enzymatically degraded very rapidly by phosphodiesterases. Compounds 6d and 7b were evaluated for antiherpesvirus effects, both in vitro and in vivo. Their antiviral spectrum and potency was remarkably similar to that of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and 9-[(2-hydroxyethoxy)-methyl]guanine (ACV), suggesting that they only act as prodrugs of BVDU and ACV, respectively. However, compound 6d did show unexpected toxicity, which could be explained by the liberation of BVDUMP following penetration of the triester into the cell.

Topics: Acyclovir; Animals; Antiviral Agents; Cells, Cultured; Chemical Phenomena; Chemistry; Deoxyuracil Nucleotides; HIV Infections; Mice; Prodrugs; Rabbits; Structure-Activity Relationship; Virus Diseases