L-696,474, a novel cytochalasin as an inhibitor of HIV-1 protease. III. Biological activity.
L-696,474, an inhibitor of the HIV-1 protease, was discovered in extracts of the fungal culture Hypoxylon fragiforme (MF5511; ATCC 20995). L-696,474 is a novel cytochalasin with a molecular weight of 477 and an empirical formula of C30H39NO4. L-696,474 inhibited HIV-1 protease activity with an IC50 of 3 microM and the mode of inhibition was competitive with respect to substrate (apparent Ki = 1 microM). Furthermore, L-696,474 was not a slow-binding inhibitor. The inhibition due to L-696,474 was also independent of the HIV-1 protease concentration. L-696,474 was inactive against pepsin, another aspartyl protease; stromelysin, a zinc-metalloproteinase; papain, a cysteine-specific protease or human leucocyte elastase, a serine-specific protease. Two other novel cytochalasins (L-697,318 and L-696,475) isolated from the same culture were inactive against the HIV-1 protease. Commercially available cytochalasins B, C, D, E, F, H and J were inactive while cytochalasin A was as active as L-696,474 against the HIV-1 protease.
Lingham
R B
RB
Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
Hsu
A
A
Silverman
K C
KC
Bills
G F
GF
Dombrowski
A
A
Goldman
M E
ME
Darke
P L
PL
Huang
L
L
Koch
G
G
Ondeyka
J G
JG
D003572:Cytochalasins / Q000494:pharmacology*; D017320:HIV Protease Inhibitors; D006801:Humans; D054833:Isoindoles; D013329:Structure-Activity Relationship
D003572:Cytochalasins; D017320:HIV Protease Inhibitors; D054833:Isoindoles; C075543:18-dehydroxycytochalasin H