FOX CHASE CHEMICAL DIVERSITY CENTER INC. — Department of Health and Human Services SBIR Phase II: R

Description

DESCRIPTION provided by applicant The smallpox virus variola has been responsible for the deaths of hundreds of millions of people worldwide Although smallpox was eradicated from the globe in following a valiant immunization campaign existing viral stocks may fall into the hands of those seeking to employ variola as a biological weapon This calls for the development of safe antiviral therapeutics that will protect unvaccinated individuals for the time required to amount an immune response to the vaccine and individuals for whom the vaccine is contraindicated Currently there are two therapeutics brincidofovir and tecovirimat which are in advanced stages of development against smallpox However drug resistant brincidofovir and tecovirimat poxvirus variants arise during infection and site directed alterations of the variola genome could be readily constructed to deliberately engineer poxvirus mutants that are resistant to both drugs Therefore it is important to develop new therapeutics that recognize different poxvirus targets Combinations of new and existing therapeutics will serve to circumvent both the natural and intentional generation of drug resistant variola We have now discovered a platform technology involving small molecules exemplified by a that inhibit infection by vaccinia virus the prototypic poxvirus and causative agent of smallpox Early lead a acts via a novel mechanism in which it binds and destabilizes the vaccinia processivity factor D which is required by the D A processivity heterodimer for tethering the viral polymerase to the DNA template to enable processive or extended strand synthesis Importantly in the case of viral processivity factors there are no cellular homologues making them excellent drug targets Moreover our evidence indicates that early lead a may be broad spectrum for all poxviruses but not for other DNA viruses Our goal is to employ medicinal chemistry to optimize ADMET PK and other properties while retaining improving antiviral potency and creating new composition of matter intellectual property strategically mutate D at structurally defined residues to elucidate its binding mechanism which will also help further guide medicinal chemistry examine the Broad Spectrum potential of our top optimized lead compounds for inhibition of several other poxviruses including monkey pox another bio threat and evaluate the final top optimized compounds for their ability to protec mice against lethal poxvirus challenge By the end of this SBIR Phase II period of study our goal is to have identified one or more preclinical drug candidates with validated antiviral potency and safety ADME PK and other required pharmaceutical criteria prior to conducting the pre clinical development under the Animal Rule required prior to filing an Investigational New Drug IND application with the U S FDA as smallpox countermeasures that may also provide broad spectrum antiviral activity against other poxviruses PUBLIC HEALTH RELEVANCE Smallpox remains a threat to human health either accidentally or by deliberate use such as via bioterrorism We are conducting a systematic program of study to obtain oral therapeutics to treat smallpox acting by a novel mechanism involving blockade of the viral processivity factor D