Chemistry Reference
In-Depth Information
TABLE 9-12. Structures and Activities of Bifunctional Betulinic Acid Derivatives
95
H
H
N
H
O
COOH
O
H
HOOC
O
H
LH-15 (282)
H
H
N
COOH
H
(CH
2
)
10
O
O
H
HOOC
O
H
LH-55 (283)
EC
50
(mM)
NL4-3
PI-R
RTI-R
DSB (263)
0
:
096
0
:
012
1
:
71
0
:
15
0
:
085
0
:
008
IC9564 (257)
0
:
11
0
:
02
0
:
12
0
:
03
0
:
093
0
:
016
LH15 (282)
0
:
0065
0
:
0008
0
:
032
0
:
004
0
:
01
0
:
001
LH55 (283)
0
:
016
0
:
003
0
:
049
0
:
005
0
:
019
0
:
003
NL4-3 is a wild-type strain; PI-R is a multiple PR inhibitor resistant strain, HIV-1 M46I, L63P, V82P, and
I84V; and RTI-R is an HIV-1 strain, HIV-1 RTMDR1 (M41L, L74V, V106A, and T215Y, resistant to
multiple HIV-1 RT inhibitors.
position-28. In a fusion assay, the potency of LH55 against NL4-3 envelope-
induced membrane fusion was similar to that of IC9564 (257) and T20, the latter
of which is the first FDA-approved fusion inhibitor for the treatment of AIDS. HIV-1
particles produced in the presence of LH55 were lysed and analyzed using Western
blots. P25 accumulated in the virus was produced in the presence of LH55. The
unique mode of action of DSB or LH55 is that these compounds affect the proces-
sing of only p25. These compounds do not affect the processing of other Gag pro-
teins, such as p17. The antifusion activity allows LH55 to block HIV-1 before it
enters the cell, whereas the antimaturation activity of this compound can combat
any virus that does enter the cell. Because the molecular targets of these bifunc-
tional anti-HIV betulinic acid derivatives are different from those of clinically
available anti-HIV drugs, it is possible that LH55 (283) and derivatives might
have the potential to become useful additions to current anti-HIV therapy.
94
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