Development and Testing of New Medications for the Treatment of Emerging Infectious Diseases [I]

Investigator: Philip J. Rosenthal, MD
Sponsor: University of Mississippi

Location(s): United States


For the past 20 years we have been actively involved in research aimed specifically at Neglected Diseases and/or Emerging Infectious Diseases with funding from the Department of Defense (DOD), Walter Reed Army Institute of Research (WRAIR), Defense and Research Programs of the Army (DARPA), World Health Organization (WHO), and National Institute of Allergy and Infectious Diseases (NIAID)~having now brought forward successful projects into funding supported by the Centers for Disease Control and Prevention (CDC). Major goals have been to utilize infrastructure support provided by CDC for the realization and functioning of the laboratory for applied drug design and synthesis (LADDS). the Department centered research facility addresses the design, synthesis and bioassay ofbroad-spectrum anti-infective agents. Two major classes of targets have been ligand based: a) the naturally occurring peroxy-sesquiterpene artemisinin, for which complex mechanisms are still to be elucidated; and b) biological targets that are widely utilized and somewhat homologous such as the proteases from these disease organisms. Overthe past year we have been very productive and somewhat fortunate in at last discovering a class of artemisinin analogs that fulfill the algorithm seemingly required to transition neglected Diseases leads to drug Development candidates (not to exclude antimalarial leads). These include Leishmania, Trypanosomiasis, Schistosomiasis, T. gondii, Babeseosis, and so on. the so called 7beta- hydroxyartemisinin microbial metabolites can be produced in high yields. We have nontoxic antigiardial derivatives ofnaturally occurring isoflavones that are being fine tuned for intestinal delivery, and are inexpensive to prepare. We are targeting the DXR pathway only found in microorganisms, such as tuberculosis. We have over the last year or so taken on significant efforts to design and test antiviral agents against SARS protease, and are taking on human rhinoviral protease, avian flu viral DNA polymerase/serine protease subunit, and Hepatitis B DNA polymerase by a variety of computer aided techniques, virtual screening and bioassay. Finally, we have set up a fully equipped, manned and trained GLP pharmacokinetics (PK) laboratory centered around a Waters triple quad, Ultra performance LCMS (Quatro- Acuity System). This allows LADDS infrastructure to inch forward now to the last stages of drug Development that are achievable with academic economics.