SBIR-STTR Award

There is a pressing need for new anti-HIV drugs that are effective against strains of the virus resistant to current regimens. Panacos Pharmaceuticals is collaborating with Professor K.H. Lee of the University of North Carolina at Chapel Hill to discover such compounds by screening plant extracts for HIV inhibitors, then designing synthetic analogs with improved antiviral and solubility properties. Dimethyl succinyl betulinic acid (DSB) is one of the most promising HIV drug candidates discovered in this collaboration. DSB potently inhibits replication by primary HIV-1 isolates and has a novel mechanism of action compared with approved drugs. Importantly, DSB is orally bioavailable with a half life of several hours in rats. The goal of this Phase I project is to determine DSB's suitability for further development. Proposed studies include: Analyzing antiviral activity against drug resistant HIV-1 strains; Elucidating mechanism of action; Studying DSB's metabolism in different species using in vitro liver microsome assays; Initiating formulation development; and extending the in vivo disposition, pharmacokinetic and metabolism analyses with DSB. An analog of DSB, dimethyl succinyl dihydrobetulinic (DSD), will also be studied in the metabolism and in vivo experiments, to provide an alternative development candidate if required. PROPOSED COMMERCIAL APPLICATIONS: The results of this Phase I SBIR project will be used to determine DSB's suitability for progressing into formal pre-clinical safety studies and initial clinical testing during the Phase II grant period. DSB has a novel mechanism of action compared with approved HIV drugs and may offer considerable potential as a new drug candidate for use in combination therapy of HIV/AIDS.

Thesaurus Terms:
antiAIDS agent, antiviral agent, drug design /synthesis /production, drug metabolism, human immunodeficiency virus, plant extract, terpene liver cell, microsome, pharmacokinetics laboratory rat

There is a pressing need for new drugs to treat HIV infection by virus strains that are resistant to the approved reverse transcriptase and protease inhibitors. Panacos Pharmaceuticals' approach to overcoming drug resistance involves identifying HIV drug candidates with novel mechanisms of action. In collaboration with Professor K.H. Lee of The University of North Carolina at Chapel Hill, Panacos has identified a promising HIV inhibitor, dimethyl succinyl betulinic acid (DSB). DSB potently inhibits HIV replication in vitro and is orally available in rats with a half-life of several hours. During the past few months, new data have been generated on DSB that provide a compelling case for the continued development of this compound. Of particular importance, it has been shown that DSB is the first in a new class of HIV drug candidates that block the last stage in the virus life cycle: budding/maturation. Furthermore, in vitro assays have demonstrated that DSB retains its nanomolar inhibitory activity against drug resistant strains of HIV, including isolates resistant to the three classes of approved drugs. This Phase II SBIR proposal has two major goals: First to identify DSB's molecular target. Mechanism of action studies will focus on targets that have been shown to play a role in HIV budding/maturation and will include determining the effect of DSB on: gag processing (p24-p2 cleavage); interaction between TSG 101 and the gag L domain; RNA dimerization; and cyclophilin incorporation into virions. The second goal is to complete pre-clinical testing of DSB, file an IND and initiate clinical testing of the novel drug candidate, focusing on the study of pharmacokinetics and safety in uninfected volunteers. If the results of pre-clinical testing indicate that DSB does not have suitable properties for clinical development, it will be replaced by a suitable analog generated during the project. The results of initial clinical studies in normal volunteers will be used as the basis to plan and perform efficacy studies in HIV-infected individuals that will be carried out subsequent to the Phase II grant period.

Thesaurus Terms:
antiAIDS agent, antiviral agent, drug design /synthesis /production, drug metabolism, human immunodeficiency virus, pharmacokinetics, plant extract, terpene HIV infection, clinical trial phase I, liver cell, microsome SCID mouse, clinical research, dog, human subject, laboratory rat, patient oriented research