Exploring Chemical Optimization Pathways for HIV-1 Env-Targeting Entry Inhibitors

Abstract

Entry of HIV-1 virus into human CD4 positive cells is a critical step for infection1. Preventing this entry process is key for therapeutic intervention. Despite advances in AIDS treatment, shortcomings in current Highly Active Anti-Retroviral Therapy (HAART) exist, such as emergent viral resistance and low patient compliance. To date, an anti-HIV-1 vaccine has not been attained. We have previously demonstrated that peptide triazoles (PTs) and their cyclic counterparts (cPTs) effectively compete for human CD4 and co-receptor binding, thus preventing infection2-3. Additionally, cPT derivatives irreversibly inactivate3 HIV-1 virions and are non-cytotoxic2. While previous optimization studies have been performed on lead cPT compounds2, enhancement of potency has been unable to yield IC50 values below 0.1[mu]M (100nM) thus far. In this study, the examination of two chemical routes for improvement of cPT potency against HIV-1 infection were investigated. Changes to the stereochemistry of the peptide backbone were tested in many sequences to yield information about structural tolerance to cPT stereochemistry. Previously, linear PTs were covalently linked4 to a co-receptor inhibitor (coRi) compound developed by collaborators5 to form a potent and synergistic chimera. Thus, the covalent attachment of a cPT to this coRi was attempted via microwave assisted solid phase peptide synthesis. Both pathways presented unique synthetic challenges which were overcome and gave much insight to the process of the solid phase synthesis technique. Neither chemical route resulted in a new lead compound with enhanced potency over the previous generation. Obtaining crystallographic data in future studies would help facilitate interpretation of these results to guide future experiments and syntheses.M.S., Chemistry -- Drexel University, 201