Furano Pyrimidines as Novel Potent and Selective Anti-VZV Agents

Bicyclic furano pyrimidine nucleosides have been found to be highly potent and selective inhibitors of varicella zoster virus (VZV). They are inactive against herpes simplex virus and have been known for several decades as (unwanted) synthetic by-products in the Pd-catalysed coupling of acetylenes to 5-iodo nucleosides. These fluorescent bicyclic nucleosides are now established as a new family of potent antivirals. They are unusual in that they exhibit complete specificity for VZV and require an alkyl (or alkylaryl) side-chain for biological activity. The latter requirement confers extremely high lipophilicities on these compounds, unknown amongst chemotherapeutic nucleosides, which may be of considerable importance in formulation, dosing and tissue distribution. The most potent compounds reported are p-alkylaryl compounds, with EC50 values below 1 nM versus VZV and selectivity index values of around 1,000,000. Here, we review the discovery, synthesis, characterization, antiviral profile, SAR, mechanism of action and development prospects for this new family of antivirals

Furano pyrimidines as novel potent and selective anti-VZV agents

Bicyclic furano pyrimidine nucleosides have been found to be highly potent and selective inhibitors of varicella zoster virus (VZV). They are inactive against herpes simplex virus and have been known for several decades as (unwanted) synthetic by-products in the Pd-catalysed coupling of acetylenes to 5-iodo nucleosides. These fluorescent bicyclic nucleosides are now established as a new family of potent antivirals. They are unusual in that they exhibit complete specificity for VZV and require an alkyl (or alkylaryl) side-chain for biological activity. The latter requirement confers extremely high lipophilicities on these compounds, unknown amongst chemotherapeutic nucleosides, which may be of considerable importance in formulation, dosing and tissue distribution. The most potent compounds reported are p-alkylaryl compounds, with EC50 values below 1 nM versus VZV and selectivity index values of around 1,000,000. Here, we review the discovery, synthesis, characterization, antiviral profile, SAR, mechanism of action and development prospects for this new family of antivirals

Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster virus

Objectives To progress the anti-varicella-zoster-virus (VZV) aryl bicyclic nucleoside analogues (BCNAs) to the point of Phase 1 clinical trial for herpes zoster. Methods A new chromatography-free synthetic access to the lead anti-VZV aryl BCNAs is reported. The anti-VZV activity of lead Cf1743 was evaluated in monolayer cell cultures and organotypic epithelial raft cultures of primary human keratinocytes. Oral dosing in rodents and preliminary pharmacokinetics assessment was made, followed by an exploration of alternative formulations and the preparation of pro-drugs. We also studied uptake into cells of both parent drug and pro-drug using fluorescent microscopy and biological assays. Results Cf1743 proved to be significantly more potent than all reference anti-VZV compounds as measured either by inhibition of infectious virus particles and/or by viral DNA load. However, the very low water solubility of this compound gave poor oral bioavailability (?14%). A Captiso

Resistance of New Zealand Provenance Leptospermum scoparium, Kunzea robusta, Kunzea linearis, and Metrosideros excelsa to Austropuccinia psidii

Resistance to the pandemic strain of Austropuccinia psidii was identified in New Zealand provenance Leptospermum scoparium, Kunzea robusta, and K. linearis plants. Only 1 Metrosideros excelsa-resistant plant was found (of the 570 tested) and no resistant plants of either Lophomyrtus bullata or L. obcordata were found. Three types of resistance were identified in Leptospermum scoparium. The first two, a putative immune response and a hypersensitive response, are leaf resistance mechanisms found in other myrtaceous species while on the lateral and main stems a putative immune stem resistance was also observed. Both leaf and stem infection were found on K. robusta and K. linearis plants as well as branch tip dieback that developed on almost 50% of the plants. L. scoparium, K. robusta, and K. linearis are the first myrtaceous species where consistent infection of stems has been observed in artificial inoculation trials. This new finding and the first observation of significant branch tip dieback of plants of the two Kunzea spp. resulted in the development of two new myrtle rust disease severity assessment scales. Significant seed family and provenance effects were found in L. scoparium, K. robusta, and K. linearis: some families produced significantly more plants with leaf, stem, and (in Kunzea spp.) branch tip dieback resistance, and provenances provided different percentages of resistant families and plants. The distribution of the disease symptoms on plants from the same seed family, and between plants from different seed families, suggested that the leaf, stem, and branch tip dieback resistances were the result of independent disease resistance mechanisms