Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog.
(Me-Ile-4)cyclosporin (SDZ NIM 811) is a 4-substituted cyclosporin which is devoid of immunosuppressive activity but retains full capacity for binding to cyclophilin and exhibits potent anti-human immunodeficiency virus type 1 (HIV-1) activity. SDZ NIM 811 selectively inhibits HIV-1 replication in T4 lymphocyte cell lines, in a monocytic cell line, and in HeLa T4 cells. Furthermore, its antiviral activity against laboratory strains and against clinical isolates from geographically distinct regions in primary T4 lymphocytes and in primary monocytes (50% inhibitory concentration = 0.011 to 0.057 micrograms/ml) was demonstrated. SDZ NIM 811 does not inhibit proviral gene expression or virus-specific enzyme functions, either free or bound to cyclophilin. The compound does not influence CD4 expression or inhibit fusion between virus-infected and uninfected cells. SDZ NIM 811 was, however, found to block formation of infectious particles from chronically infected cells. Oral administration to mice, rats, dogs, and monkeys resulted in levels in blood considerably exceeding the drug concentration, which completely blocked virus replication in primary cells. SDZ NIM 811 caused changes of toxicity parameters in rats to a smaller degree than cyclosporine (formerly cyclosporin A). Thus, the potent and selective anti-HIV-1 activity of SDZ NIM 811 and its favorable pharmacokinetic behavior together with its lower nephrotoxicity than that of cyclosporine make this compound a promising candidate for development as an anti-HIV drug.
Rosenwirth
B
B
Sandoz Forschungsinstitut GmbH, Vienna, Austria.
Billich
A
A
Datema
R
R
Donatsch
P
P
Hammerschmid
F
F
Harrison
R
R
Hiestand
P
P
Jaksche
H
H
Mayer
P
P
Peichl
P
P
D000591:Amino Acid Isomerases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus