Antiviral Resistance to Acyclic Phosphonates in Orthopoxviruses

PROJECT SUMMARY Mpox, caused by the orthopoxvirus mpox virus (MPXV), became an infectious disease of worldwide concern following a 2022 global outbreak in which more than 80,000 cases were confirmed in more than 100 countries, mostly in countries outside the endemic regions of West and Central Africa. As reported in April 2024, there are currently record numbers of infections in the Democratic Republic of Congo, nearly 400 suspect cases reported each week. The circulating strain appears particularly deadly, with ~1 in 10 patients dying, appears to spread in new ways, and is able to evade diagnostic testing. Because of this and the risk of future outbreaks and global spread of mpox, there is a need to be prepared through the development of antiviral therapies targeting MPXV. Current therapies, comprised of tecovirimat (TPOXX), cidofovir (CDV), and brincidofovir, have concerns with toxicity and potential for emergence of drug resistance. Therefore, there are currently no mpox treatments that are both highly potent and well-tolerated. Research done by our lab has shown that the repurposed compounds tenofovir alafenamide (TAF) and adefovir dipivoxil (ADF), which are acyclic nucleoside phosphonates, inhibit MPXV. However, these compounds should be tested for the potential for antiviral resistance to emerge before they could be used in animal studies and clinical trials. In this proposal, my goals are to (Aim 1) identify and validate mutations in orthopoxviruses that confer resistance to acyclic phosphonates, (Aim 2) characterize the biochemical mechanisms of inhibition by and resistance to acyclic phosphonates, and (Aim 3) evaluate combination therapies to prevent the emergence of resistance. These studies will reveal how orthopoxviruses evolve resistance to TAF and ADF, give insights into downstream studies to minimize potential for resistance, and further my training and skills as an independent research scientist.