|
|
Abstract
Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule protease dimerization inhibitors
Koh Y.1, Matsumi S.1, Amano M.1, Das D.2, Davis D.A.3, Li J.4, Leschenko S.4, Baldridge A.4, Shioda T.5, Yarchoan R.3, Ghosh A.K.4, Mitsuya H.2
Objectives: Dimerization of HIV-1 protease subunits is an essential process for the acquisition of proteolytic activity of HIV-1 protease, which plays a critical role in the replication cycle of HIV-1. Hence, the inhibition of dimerization of HIV-1 protease subunits represents a unique target for potential intervention of HIV-1 replication.
Methods: An intermolecular fluorescence resonance energy transfer (FRET)-based HIV-1-expression assay that employs cyan and yellow fluorescent protein (CFP and YFP)-tagged HIV-1 protease monomer subunits was generated to evaluate the disruption of HIV-1 protease dimerization.
Results: We identified a group of non-peptidyl small molecule inhibitors of HIV-1 protease dimerization (M.W.: 547-704). These inhibitors, including 3 newly designed compounds, the recently approved PI darunavir, and two experimental PIs, blocked protease dimerization at concentrations of as low as 0.01 µM and blocked HIV-1 replication in vitro with IC50 values of 0.0002-0.48 µM. These agents also inhibited the proteolytic activity of mature HIV-1 protease. A 27-amino acid peptide based on the amino- and carboxy-termini of HIV-1 protease proved to block protease dimerization in this assay. Twelve FDA-approved anti-HIV-1 agents, including RTIs, PIs, and a CCR5 inhibitor aplaviroc failed to block the dimerization event. It appeared that once HIV-1 protease monomers dimerize to become mature protease, it is not affected by this dimerization inhibition mechanism, suggesting that these agents block protease dimerization at the nascent stage of protease. The proteolytic activity of mature protease that managed to undergo dimerization in spite of the presence of these agents is likely to be inhibited by the same agents acting as conventional protease inhibitors. Such dual inhibition mechanisms could lead to highly potent inhibition of HIV-1.
Conclusions: The present data should not only help design and examine agents that potentially inhibit HIV-1 protease dimerization, but also should give new insights into the process and dynamics of HIV-1 protease dimerization per se.
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
Abstract no.
MOPDX04
Suggested Citation
"KohY., et al.
Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule protease dimerization inhibitors.
Poster discussion:
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention:
Abstract no.
MOPDX04"
|
|
|