title: L-696,474, a novel cytochalasin as an inhibitor of HIV-1 protease. III. Biological activity.
abstract: 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.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
authors.forename: R B
authors.initials: RB
authors.lastname: Lingham
authors.forename: A
authors.initials: A
authors.lastname: Hsu
authors.forename: K C
authors.initials: KC
authors.lastname: Silverman
authors.forename: G F
authors.initials: GF
authors.lastname: Bills
authors.forename: A
authors.initials: A
authors.lastname: Dombrowski
authors.forename: M E
authors.initials: ME
authors.lastname: Goldman
authors.forename: P L
authors.initials: PL
authors.lastname: Darke
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.forename: G
authors.initials: G
authors.lastname: Koch
authors.forename: J G
authors.initials: JG
authors.lastname: Ondeyka
mesh_terms: D003572:Cytochalasins / Q000494:pharmacology*; D017320:HIV Protease Inhibitors; D006801:Humans; D054833:Isoindoles; D013329:Structure-Activity Relationship
chemical_list: D003572:Cytochalasins; D017320:HIV Protease Inhibitors; D054833:Isoindoles; C075543:18-dehydroxycytochalasin H