Preclinical Development of 2nd Generation HIV Maturation Inhibitors

Project SummaryDespite advances in the development of HIV drugs there remains a need for
new therapiesToxicities associated with long term use of many of the approved HIV drugs
coupled with the development of resistance drives the need for new and novel antiviralsMaturation inhibitorsMIsrepresent one such class of HIV therapiesHIV maturation inhibitors
block virus replication by disrupting the conversion of the capsid precursor proteinCA SPpto the mature form of capsidCApresulting in the formation and release of noninfectious viral particlesUnlike protease inhibitors that bind to and inhibit the action of the viral
proteaseMIs directly target the HIVGag proteinThis novel mechanism of action allows MIs
to retain full activity against viruses that have developed resistance to approved classes of HIV
drugsClinical proof of concept for maturation inhibitors was established with the first in class
MIbevirimatBVMIn a series of trialsBVM was shown to be safe and effective in reducing
HIV viral load in infected individualshowevera lack of uniform patient response was also
observedAnalysis of patient virus revealed that a single amino acid polymorphism in the SPregion of the viral Gag protein was a primary determinant of patient responseThis
polymorphism involves a Val to Ala change at SPamino acidV AApproximatelyof
HIVisolates contain Vand are highly sensitive to BVM while the remainingcontain Aand lack sensitivityAs a result of this observationclinical development of BVM was terminatedDFH Pharmaandapos s current efforts focus on the identification of next generation MIs with broad antiHIV activitySpecificallywe have identifiednd generation MIs that exhibit potent activity
against a range of HIV isolatesUnlike the restricted activity observed with BVMthesend
generation analogs inhibit a broad variety of group M subtypesgroup N and O viruses and
isolates resistant to currently approved HIV drugsRecent testing has determined that the most
potent of these broadly active compounds exhibit ICvalues in the single digit to low double
digit nM rangeThis activity level is within the accepted range for HIV drug development
candidates and compares favorably with the Bristol Myers SquibbBMSMI clinical candidateThe focus of the current application is to build on this success and continue the effort to identifynd generation MIs suitable for development as HIV drugsHaving identified compounds that are
both highly potent and broadly active the objective of the proposed work involves further
characterization of the drug development potential of the most promising compounds to selectnd generation MIs to advance into IND enabling pre clinical studies Project NarrativeDespite advances in the development of HIV drugs there remains a need for
new therapiesMaturation inhibitors represent one class of new HIV therapiesDFH Pharma is
focusing on the characterization and development of a new generation of maturation inhibitors
for use as HIV therapeutics