Riboscience LLC — Department of Health and Human Services SBIR Phase II: R

Description

Our goal is to leverage our excitingSBIR Phaseequivalentresearch results into a novel nucleoside based treatment for Zika virusZIKVthat can be used for prevention or treatment of ZIKV infectionOur lead moleculeRBSis the first potent and specific inhibitor of ZIKV replicationECmicromolarCCandgtmicromolarand that is suitable for the development of both oral and intravenous dosage formsRBSis a prodrug that improves delivery of the nucleosideAU to infected cellsAU has already shown safety in chronic toxicity studies in rats and monkeys and in a Phaseclinical study performed in healthy volunteers and HCV patients at doses up tomg and up toweek treatment durationWe now seek to develop RBSas an improved prodrug ofAU into a clinical stage drug byoptimizing the process chemistry route to synthesize larger quantities of RBSand synthesizing scale up batches to support in vitro and in vivo characterizationg andgcompleting the antiviral characterization of RBSin vitro and in vivo in ZIKV mouse models and in vitro resistance characterization including the testing against available ZIKV strains in cell culture including multiple primary human cellsdetermining efficacy in protecting mice from systemic spread of infectioninfection of pregnant mice and impact of timing of treatment startpassaging RBSin Huhcells at increasing drug concentrations to select resistant ZIKV variants and generating recombinant ZIKV polymerase to confirm resistance mutationsdetermining key in vitro pharmacology and preclinical safety parameters of RBSincluding permeability in Cacocells and cytotoxicity in primary human cells and formation and half life ofAU triphosphate in human target cellsand in animal cellsmouseratdogdetermining the in vivo pharmacokinetics and initial toxicity profile of RBSin single dose PK studies in two speciesrats and dogsin in vitro safetygenotoxicity and ADME studiesincluding CYP and transporter inhibition assayshERG inhibitionAMESMNTchromosomal aberration testingmetabolic stabilityand safetyCVrespiratoryand CNSprofiling andday non GLP toxicity studiessynthesizing akg GMP grade batch of RBSand performweek GLP toxicity studies and safety pharmacology studies to enable INDOur team is highly experienced in successful drug discovery and developmentIn additionthis team is expert in the synthesis and characterization of selectiveefficacious and safe nucleoside analogs for viral diseasesThis team is therefore well positioned to deliver a highly innovative potentselectivewell toleratedeasy to use inhibitor of ZIKV replicationtargeting the ZIKV polymerase with high barrier to resistance capable of providing prophylactic and therapeutic protection against this serious pathogen There is a great need for new drugs that could be used for both prophylaxis and treatment of Zika virus infectionsWe have developed a new lead nucleoside analog with potent activity against Zika virus polymerase without host cell toxicityVia a highly experienced multidisciplinary team and collaboratorswe now seek to leverage this exciting research to date into a clinical stage pangenotypic drug with a high barrier to resistance capable of protecting people from Zika virus and its complications