Elucidation of TPV's protease dimerization inhibition (PDI) mechanism and development of potent compounds possessing PDI activity

2014 Fiscal Year Final Research Report

• Project/Area Number: 24791031
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto Health Science University
• Principal Investigator: AOKI Manabu 熊本保健科学大学, 保健科学部, 講師 (70389542)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: HIV / プロテアーゼ阻害剤 / 薬剤耐性

Outline of Final Research Achievements

Tipranavir(TPV), a protease inhibitor, has protease dimerization inhibition(PDI)activity. 31 TPV-related resistance mutations were examined to determine whether those mutations affect TPV’s PDI activity. 17 of those mutations reduced TPV’s PDI activity and located in three PR regions critical for PR monomer folding. Furthermore, tests were conducted to determine if TPV binds to monomer PR subunits by using ESI-MS. The tests suggest that TPV binds to both monomer and dimer PR, indicating that TPV likely inhibits PR dimerization through binding to monomer PR subunits. 14 tripeptides carrying identical amino acid sequences as the aforementioned three regions affecting TPV’s PDI activity were synthesized and examined for their influence on PDI activity. Some of the tripeptides were shown to inhibit PR dimerization. Further studies on the mechanisms of dimerization inhibition by compounds should provide better insights required for developing more potent protease dimerization inhibitors.

Free Research Field

ウイルス学