Novel synthetic TLR4 agonists

Project SummaryThere are currently no approved vaccines for most emerging biological pathogensEbolaChikungunyaMERS CoVSARSZikaopportunistic infectionsSaureusCandidiasisadenovirusor potential bioterrorism agentsYpestisBPseudomalleiFtularensisBunyaviridaeFlaviviridaeand therapeutic interventions such as antibiotics and antivirals are only effective for a select few pathogensA promising approach for rapidly neutralizing the risk of pathogen exposure is the use of immunomodulators capable of eliciting a robust innate immune response within hours of administration that would provide protective resistance against a wide range of biological agentsInnate immunity has evolved as a first line of defense against invading pathogens and acts through highly conserved patternrecognition receptors such as Toll like receptorsTLRto coordinate the innate inflammatory response to both endogenous and exogenous stimuliThe objective of this Phase I research proposal is to initiate an investigation of structure activity relationships within a new class of chemically and metabolically more stable synthetic TLRagonists in order to identify the structural requirements for the development of a broad spectrum immunomodulator that would provide non specific protective resistanceNSRagainst a wide range of biological agentsIn addition to potentially providing weeks long NSR against a wide range of viruses and bacteriathe improved stability profile of these synthetic immunomodulators should improve thermal stability leading to a longer shelf life and avoidance of cold chain requirements for distributionAimwill focus onithe synthesis of six new TLRagonists in which the labile ester and phosphate groups are replaced with more stable bioisostersandiievaluation of the stability of these new agonists in aqueous formulationsAimwill evaluate the biological activity of the new compounds in vitro foriTLRspecies specificity and potency in a TLRspecific reporter assay andiicytokine induction from human peripheral blood mononuclear cellsThis phase I research proposal and subsequent phase II have the potential to develop broadspectrum immunomodulators that would provide non specific protective resistanceNSRagainst a wide range of biological agentsand is primarily targeted for preventing upper respiratory tract infections in individuals or populations at risk for emerging or opportunistic pathogen exposureSuch treatment could help prevent deaths associated with seasonal or pandemic influenza viruses as well as other respiratory pathogens of significant medical concern Project NarrativeThere are currently no approved vaccines for most emerging biological pathogensEbolaChikungunyaMERS CoVSARSZikaopportunistic infectionsSaureusCandidiasisadenovirusor bioterrorism agentsYpestisBPseudomalleiFtularensisBunyaviridaeFlaviviridaeand therapeutic interventions such as antibiotics and antivirals are only effective for a select few pathogensA promising approach for rapidly neutralizing the risk of pathogen exposure is the use of immunomodulators capable of eliciting a rapid robust innate immune response that would provide protective resistance against a wide range of biological agentsThe objective of this Phase I research proposal is to initiate an investigation of structure activity relationshipSARwithin a new class of chemically and metabolically more stable synthetic Tolllike receptorTLRagonists for the development of a safe self administered intranasal broadspectrum immune therapeutic with effective anti viral and anti bacterial activity to prevent upper respiratory tract infections in individuals or populations at risk for emerging or opportunistic pathogen exposure