Vaccines 2017-Prodrugs as a Strategy for More Effective Anti-Adenovirus Agents- Charles E McKenna - University of Southern California

Human adenoviruses (AdV) cause generally mild infections of the respiratory and GI tracts still as another tissues. However, certain serotypes are related to acute respiratory dis-ease and epidemic keratoconjunctivitis.  AdV can cause serious infection in severely immunosup-pressed individuals, and pediatric patients undergoing allogeneic hematopoietic stem cell transplan-tation have mortality rates up to 80% with disseminated disease. Despite this significant challenge to health, there aren't any drugs approved specifically to treat AdV infections.

Nucleoside analogue origins of recent antiviral chemotherapy In the 21st century, antiviral chemotherapy is well established for the prevention and treatment of the many important virus infections; there are now quite 40 licensed drugs for diseases caused by herpesviruses, retroviruses, orthomyxoviruses, hepatitis B and viral hepatitis viruses. Without exception, all viruses are obligate, intracellular parasites and until the 1950s were widely believed to not be vulnerable to ‘antibiotic' therapy. This dogma was reversed with the invention of 5-iodo-2′-deoxyuridine (idoxurine), the primary medicament to be widely used having acknowledged clinical utility for the topical treatment of herpes keratitis. For the following 20 years, the sector of antiviral therapy was dominated by this and other nucleoside analogues especially trifluorothymidine, adenine arabinoside and subsequently acyclovir (ACV), bromovinyldeoxyuridine, ganciclovir and penciclovir. Antiviral nucleosides as prodrugs All these nucleosides are essentially ‘prodrugs' since their antiviral activity depends upon metabolism within herpes-infected cells to create sequentially the mono-, di- and triphosphates (MP, DP, and TP, respectively). it's these nucleotides (especially the nucleoside TP) that inhibit essential processes in virus replication. most vital, the nucleoside TP may inhibit herpesvirus-encoded DNA-polymerase. Furthermore, some nucleoside TPs (notably ACV-TP) are obligate chain terminators of herpesvirus DNA while others (notably penciclovir-TP) could also be facultative chain terminators (Wutzler & Thust, 2001) but in most cases virus DNA replication is blocked (Darby, 1995). For the aim of this review, however, ‘antiviral prodrug' are defined as a compound that needs metabolic conversion in vivo before entering the infected cell wherein further metabolism may or might not be required to yield the active inhibitor. First- and second-generation nucleoside analogues the first-generation antiviral nucleosides (including idoxuridine and trifluorothymidine) were poorly selective for virus-infected cells and proved to be too toxic for systemic administration; they are used just for topical application. a significant advance occurred with the invention that ACV – the primary of the second-generation nucleoside analogues – may be a highly selective inhibitor of herpes simplex virus (HSV-1) and varicella-zoster virus (VZV), and, moreover, safe for oral administration. The development of antiviral prodrugs The discovery of ACV as a selective antiherpetic agent heralded a replacement era in antiviral chemotherapy, that of a selective approach to attack virus infections. ACV would, later on, become the gold standard for the treatment of herpesvirus (HSV-1, HSV-2 and VZV) infections. The compound (first referred to as acycloguanosine) was synthesized within the U.S.A. as a part of the Burroughs Wellcome programme for the event of guanosine nucleosides immune to phosphorylase degradation with the primary observation of antiviral activity being made by Collins & Bauer within the U.K. at the Beckenham laboratories of the previous Wellcome Foundation. The key to selectivity was subsequently shown to be selective phosphorylation of the acyclic guanosine nucleoside, ACV to ACV-MP by the herpesvirus-encoded pyrimidine deoxynucleoside kinase, thymidine kinase (TK). Further highly selective nucleosides with similar mechanisms of selectivity followed with the reports of bromovinyldeoxyuridine (BVDU), ganciclovir (GCV) and penciclovir (PCV). While these and similar compounds were very effective inhibitors of HSV in cell culture with effective inhibitory concentrations of 1 μm or lower and ACV proved safe for systemic administration, there remained a crucial disadvantage; that of relatively low oral bioavailability and short plasma half-life. Comparatively large doses and frequent administration were thus required to keep up trough values for plasma concentrations of ACV above the brink required for virus inhibition. Thus, ACV has limited oral bioavailability (15–20%); possibly as low as 10% following an 800 mg dose and also limited solubility in water (∼0.2%, 25°C). this implies that the compound cannot be given as intramuscular injections (and therefore must be administered intravenously as a bolus infusion of 5 mg kg−1 every 8 h), or, for the treatment of herpetic keratitis, can't be given as eyedrops (and therefore must be applied as a third eye ointment). In attempts to create ACV more water soluble, several ester derivatives of ACV were prepared, taht is, 2′-O-glycyl and 2′-O-alanyl ACV esters. The 2′-O-glycyl ester proved to be efficacious within the topical treatment of herpetic keratitis (in rabbits) when administered as a tenth eyedrop formulation and, because the patent of ACV drew towards its end and generic ACV was to become widely available, much try was directed to boost methods of drug delivery including methods of slow release by mechanical or chemical methods leading ultimately to the primary successful antiviral prodrugs. Antiviral nucleosides as prodrugs All these nucleosides are essentially ‘prodrugs' since their antiviral activity depends upon metabolism within herpes-infected cells to create sequentially the mono-, di- and triphosphates (MP, DP, and TP, respectively). it's these nucleotides (especially the nucleoside TP) that inhibit essential processes in virus replication. most vital, the nucleoside TP may inhibit herpesvirus-encoded DNA-polymerase. 

Note- This work is partly presented at 20th Global Summit & Expo on Vaccines, Immunization & B2B September 18-19, 2017 Houston, USA.

Author(s): Charles E McKenna

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