Judith M. LaLonde, Arne Schön, Navid Madani, Amy M. Princiotto, Mark A. Elban, Joel R. Courter, Akihiro Sugawara, Takahiro Soeta, David M. Jones, Alexander W. Sun, Amos B. Smith, Joseph Sodroski and Ernesto Freire
Scientific Tracks Abstracts: JAA
The low-molecular-weight compound TS-II-224 inhibits infection of HIV-1 by blocking the binding of the viral envelope glycoprotein gp120 to the CD4 receptor and is therefore an important lead as a viral entry inhibitor. Virtual screening and synthesis eff orts were used to fi nd substitutes for the Region III tetramethylpiperidine moiety of TS-II-224. Th ese Region III analogs exhibit similar inhibitory activity but bind with diverse thermodynamic signatures. Similar binding affi nities can be achieved by diff erent combinations of entropic and enthalpic contributions. However these contributions have functional consequences in the extent of gp120 structuring and the sensitivity to activation of viral infectivity. Th ese compounds demonstrate that gp120 binding affi nity, structuring and viral infectivity are dramatically aff ected by interactions between Region III and the amino acid residues in the vestibule of the gp120 Phe 43 cavity. Analogs that bind within the Phe 43 cavity without driving gp120 structural changes are suitable platforms for further optimization as HIV entry inhibitors.
