Polyanion inhibitors of HIV and other viruses. 7. Polyanionic compounds and polyzwitterionic compounds derived from cyclodextrins as inhibitors of HIV transmission.
New polyanionic compounds were obtained from radical addition of thiomalic acid and mercaptopropionic acid onto perallylated cyclodextrins (CDs) under UV irradiation with a catalytic amount of alpha,alpha'-azobis(isobutyronitrile). All these polyanions, bearing 18-48 carboxylate groups, inhibited human immunodeficiency virus type 1 (HIV-1) strain IIIB replication in MT-4 cells at a 50% inhibitory concentration (IC50) of 0.1-2.9 microM, while not being toxic to the host cells at concentrations up to 62 microM. These compounds were also active against a clinical HIV-1 isolate (HE) at >/=4-fold higher concentrations. Only some compounds showed activity against the two HIV-2 strains (ROD and EHO) but at higher concentrations than those required to inhibit HIV-1 (IIIB and HE) replication. In addition, these compounds were not active against the M-tropic HIV-1 strain BaL but were active against simian immunodeficiency virus [SIV (MAC251)]. These compounds were also inhibitory to the replication of human cytomegalovirus at an IC50 of 1-10 microM, but not herpes simplex virus (type 1 and type 2) or other (picorna-, toga-, reo-, orthomyxo-, paramyxo-, bunya-, rhabdo-, and poxvirus) viruses. Radical addition on perallylated CDs of a protected cysteine gave polyzwitterionic compounds. None of these last compounds proved inhibitory to the replication of HIV-1, HIV-2, or any of the other viruses tested.
Leydet
A
A
Laboratoire de Chimie Organique Physique, Université Montpellier II, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
Moullet
C
C
Roque
J P
JP
Witvrouw
M
M
Pannecouque
C
C
Andrei
G
G
Snoeck
R
R
Neyts
J
J
Schols
D
D
De Clercq
E
E
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002240:Carbohydrate Sequence; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D002522:Chlorocebus aethiops; D003505:Cyclodextrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004267:DNA Viruses / Q000187:drug effects; D004285:Dogs; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification; D015498:HIV-2 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D012328:RNA Viruses / Q000187:drug effects; D013329:Structure-Activity Relationship; D014466:Ultraviolet Rays; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D002264:Carboxylic Acids; D003505:Cyclodextrins