Filociclovir Is an Active Antiviral Agent against Ocular Adenovirus Isolates In Vitro and in the Ad5/NZW Rabbit Ocular Model.

Eric G Romanowski,Terry L Bowlin,Michelle M Butler,Kathleen A Yates,Robert M Q Shanks,Islam T M Hussein,Steven C Cardinale,Regis P Kowalski,Lucas R Morin

doi:10.3390/ph14040294

Eric G Romanowski, Terry L Bowlin + Show 7 more

Open Access

https://doi.org/10.3390/ph14040294

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Abstract

Presently, there is no FDA- or EMA-approved antiviral for the treatment of human adenovirus (HAdV) ocular infections. This study determined the antiviral activity of filociclovir (FCV) against ocular HAdV isolates in vitro and in the Ad5/NZW rabbit ocular model. The 50% effective concentrations (EC50) of FCV and cidofovir (CDV) were determined for several ocular HAdV types using standard plaque reduction assays. Rabbits were topically inoculated in both eyes with HAdV5. On day 1, the rabbits were divided into four topical treatment groups: (1) 0.5% FCV 4x/day × 10 d; (2) 0.1% FCV 4x/day × 10 d; (3) 0.5% CDV 2x/day × 7 d; (4) vehicle 4x/day × 10 d. Eyes were cultured for virus on days 0, 1, 3, 4, 5, 7, 9, 11, and 14. The resulting viral eye titers were determined using standard plaque assays. The mean in vitro EC50 for FCV against tested HAdV types ranged from 0.50 to 4.68 µM, whereas those treated with CDV ranged from 0.49 to 30.3 µM. In vivo, compared to vehicle, 0.5% FCV, 0.1% FCV, and 0.5% CDV produced lower eye titers, fewer numbers of positive eye cultures, and shorter durations of eye infection. FCV demonstrated anti-adenovirus activity in vitro and in vivo.

Highlights

Human adenoviruses (HAdV) cause a variety of respiratory infections, conjunctivitis, gastroenteritis, and hemorrhagic cystitis [1]
FCV appears to inhibit human cytomegalovirus (HCMV) replication using a complex mechanism of action that involves both the inhibition of the viral UL54 DNA polymerase and the UL97 kinase [7,10]
Nucleoside analog antiviral antiviralagents agentshave have a long history of use in ophthalmology

Summary

Introduction

Human adenoviruses (HAdV) cause a variety of respiratory infections, conjunctivitis, gastroenteritis, and hemorrhagic cystitis [1]. A number of antiviral agents have demonstrated antiviral activity in vitro and antiviral efficacy in small human clinical trials [1,2]. Among these infections, HAdV ocular infections (epidemic keratoconjunctivitis (EKC), follicular conjunctivitis, and pharyngeal conjunctival fever) are the most common ocular viral infections worldwide [3,4]. Filociclovir (FCV; cyclopropavir or MBX-400) is a novel methylene-cyclopropane nucleoside analog (Figure 1) that has demonstrated broad-spectrum antiviral activity against a number of herpesviruses including several that cause ocular disease, human cytomegalovirus (HCMV), varicella zoster virus (VZV), and Epstein–Barr virus (EBV) [6,7,8]. FCV appears to inhibit HCMV replication using a complex mechanism of action that involves both the inhibition of the viral UL54 DNA polymerase and the UL97 kinase [7,10]

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