This is a Phase I proposal to develop a new family of imino sugars, with "break through", unprecedented, potency, for the treatment of dengue virus (DENV) infection. There is currently no effective treatment for diseases caused by this virus and both the public health and military need are enormous. The ultimate goal is to have a drug tested in people for safety (Phase I clinical trial) within 3 years. DENV has been shown by us and others to be extremely sensitive to imino sugars in vitro and in vivo. Development of imino sugars has been limited by low potency in vivo, due to the inability to achieve sufficient therapeutic concentrations. Our preliminary study with rationally designed chemical modifications on current lead imino sugars, has led to discovery of a novel family of compounds (PBDNJs) with sub-micromolar EC50s and selectivity indexes of more than 800 against dengue virus infection in tissue culture. These represent the best in this class and potencies are 10-20 times better than has ever been previously achieved, making it realistic to consider effective human use. In this Phase I proposal, before committing to current PBDNJs, we will systematically synthesize and test more imino sugar derivatives following the current path of chemical modification, and select candidates with equal to or better activity and cytotoxicity profile than our current lead, for absorption, distribution, drug metabolism and excretion (ADME) studies. Phase I studies will allow the selection of the 2 or 3 best compounds for advancement into phase II, which will consist of testing for toxicity and efficacy in the DENV animal model, and Phase I clinical trials in humans. Since we are co-inventors of the imino sugar antiviral technology, we are confident of our aggressive time frame.
Public Health Relevance: This is a proposal for the development into a drug of a novel family of imino sugars with breakthrough antiviral activity against dengue virus (DENV). This compound would function through interfering with virion secretion by targeting a host enzyme required for this process, and may be of use by itself or in combination with other potential candidates with different mechanism-of-action to extend efficacy. At the end of the proposed project, the novel imino sugar compound would be ready for large-scale Phase II/III clinical testing with dengue infected patients.
Public Health Relevance Statement: This is a proposal for the development into a drug of a novel family of imino sugars with breakthrough antiviral activity against dengue virus (DENV). This compound would function through interfering with virion secretion by targeting a host enzyme required for this process, and may be of use by itself or in combination with other potential candidates with different mechanism-of-action to extend efficacy. At the end of the proposed project, the novel imino sugar compound would be ready for large-scale Phase II/III clinical testing with dengue infected patients.
NIH Spending Category: Biodefense; Emerging Infectious Diseases; Infectious Diseases; Vector-Borne Diseases
Project Terms: Absorption; Acute; Animal Model; Animal Models and Related Studies; Animal Testing; Animals; Antiviral Agents; Antiviral Drugs; Antivirals; Armed Forces Personnel; Autopsy; Bioavailability; Biologic Availability; Biological Availability; Blood Serum; Breakbone Fever Virus; Cell Culture Techniques; Cells; Chemicals; Clinical Evaluation; Clinical Testing; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Commit; Common Rat Strains; Data; Dengue; Dengue Fever; Dengue Virus; Development; Disease; Disorder; Dose; Drug Formulations; Drug Kinetics; Drugs; Early-Stage Clinical Trials; Enzymes; Excretory function; Family; Formulation; Formulations, Drug; Frequencies (time pattern); Frequency; Glucosidase Inhibitor; Glycoproteins; Goals; Human; Human, General; IFN; In Vitro; Infection; Interferons; Investigational New Drug Application; Knock-out; Knockout; Knowledge; Lead; Liver Microsomes; Lytotoxicity; Mammals, Mice; Mammals, Rats; Man (Taxonomy); Man, Modern; Medication; Metabolic; Mice; Microsomes, Liver; Military; Military Personnel; Modeling; Modification; Mortality; Mortality Vital Statistics; Murine; Mus; New Guinea; Oral; Organ Weight; Outcome; Patients; Pb element; Permeability; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Physiologic Availability; Plaque Assay; Plasma Proteins; Process; Process of absorption; Protein Binding; Protocol; Protocols documentation; Public Health; Rat; Rats, Sprague-Dawley; Rattus; Receptor Protein; Research Resources; Resources; Rights; Safety; Series; Serotyping; Serum; Side; Solubility; Sprague-Dawley Rats; Structure; System; System, LOINC Axis 4; Technology; Testing; Therapeutic; Time; Toxic effect; Toxicities; Toxicity Testing; Toxicity Tests; Toxicokinetics; Viral; Viral Diseases; Viremia; Virion; Virus; Virus Diseases; Virus Particle; Viruses, General; Weight, Organ; Work; absorption; analog; animal efficacy; base; bioavailability of drug; breakbone fever; clinical investigation; clinical test; cytotoxicity; design; designing; disease/disorder; drug detection; drug metabolism; drug testing; drug/agent; effective therapy; efficacy testing; excretion; heavy metal Pb; heavy metal lead; improved; in vitro activity; in vitro testing; in vivo; indexing; model organism; mouse model; necropsy; novel; phase 1 study; phase 1 trial; phase I trial; postmortem; pre-clinical; preclinical; protocol, phase I; public health medicine (field); public health relevance; receptor; research clinical testing; stability testing; sugar; tissue culture; viraemia; viral infection; viral sepsis; virus infection; virusemia
