The filoviruses, including the Ebola viruses (EBOVs) have been at the forefront of the world's attention due to the outbreak in West Africa in 2015 that also affected US citizens. The filoviruses represent a severe threat to the global community, as they are some of the deadliest pathogens known, with fatality rates reaching as high as 90%. Moreover, there are no FDA- approved drugs or vaccines to treat them. Alarmingly, recent studies have revealed that EBOV patients that had seemingly recovered are still infected with the virus. EBOV has been found in the CNS, eyes, amniotic fluid, placenta, semen, breast milk, and most recently, the lungs. As a result, there is a clear and urgent need for effective therapeutics given the global pandemic threat they pose. Over the past few years several nucleoside analogues have been investigated as possible filovirus therapeutics including two developed in the Seley-Radtke laboratories. These compounds have exhibited broad-spectrum activity against a number of viruses, including EBOVs and coronaviruses, thus represents valid targets for additional structural modifications. In an effort to further explore our own findings as well as others, we have combined the key structural features of the sugar moieties in several nucleosides that have shown activity against EBOVs with our fleximer (?split? purine) concept. The split base modification allows the heterobase to rotate and adapt to point mutations in a binding site to maximize crucial structural interactions without losing the integrity of the functional groups required for recognition and activity. This modification has also shown promise for overcoming point mutations related to resistance mechanisms. Thus, the hope is that these ?hybrid? nucleosides will not only exhibit potent and broad-spectrum activity against the filoviruses, but also against drug-resistant strains that will likely arise in the future, due to their inherent flexibility.
The filoviruses, including the Ebola viruses (EBOVs) represent a severe threat to the global community, as they are some of the deadliest pathogens known, with fatality rates reaching as high as 90%. This project focuses on exploring a series of hybrid nucleosides that have shown preliminary potent activity against several EBOVs.
