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UIC-02031: A Novel Nonpeptidic Protease Inhibbitor Containing a Stereochemically Defined Fused Cyclopentanyltetrahydrofuran Potent against Multi-PI-Resistant HIV-1 in vitro
Yasuhiro Koh*1, H Nakata1, H Ogata-Aoki1, S Leschenko2, A Ghosh2, and H Mitsuya1,3
1Kumamoto Univ Sch of Med, Japan; 2Univ of Illinois at Chicago, USA; and 3NCI, NIH, DHHS, Bethesda, MD, USA
Background: The rapid rise of protease inhibitor
(PI)-resistant HIV-1 variants urges the development of new classes of PI, which
are potent against existing resistant HIV-1 variants and do not allow or delay
the emergence of resistance. We generated a novel non-peptidic
PI, UIC-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran
(Cp-THF), which exerted potent activity against a wide spectrum of HIV-1
including multi-drug-resistant HIV-1 variants (HIVMDR).
Methods: Each PI (saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir)-resistant
HIV-1 variants was selected in vitro
by propagating HIV-1 in the presence of increasing concentrations of PI using
MT-4 cells. Anti-HIV-1 activity of the compound was determined using MTT assay
employing MT-2 cells and p24 assay using PHA-stimulated
PBM or MT-4 cells.
Results: UIC-02031 was highly potent
against laboratory HIV-1 strains and primary clinical isolates including
subtype A ,B, C, and E (IC50: 0.015-0.038 µM) with minimal cytotoxicity (CC50: >100 µM in CD4+
MT-2 cells), although it was less active to 2 HIV-2 strains (HIV-2EHO
and HIV-2ROD) (IC50: ~0.60 µM). UIC-02031
at relatively low concentrations (IC50: 0.036 to 0.14 µM) blocked
the infection and replication of each of HIV-1NL4-3 variants exposed
to and selected by up to 5 µM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir. UIC-02031 was also potent against
multi-PI-resistant clinical HIV-1 variants isolated from patients who had no
response to existing antiviral regimens after having received a variety of
antiviral agents with IC50 values ranging from 0.014 to
0.042 µM (< 2-fold changes in IC50 compared with that of wild type
HIV-1). Upon selection of HIV-1NL4-3 in the presence of
UIC-02031, mutants carrying L10F,
L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region
and G62R (p17), L363M (p24/p2 cleavage site), R409K (p7), and I437T (p7/p1
cleavage site）in the Gag-encoding region
emerged.
Conclusions: The data warrant that UIC-02031
is further developed as a potential therapeutic agent for treatment of
infection with primary and multi-drug-resistant HIV.
Keywords: Protease inhibitor; multi-drug-resistant HIV-1; drug design
