Inhibition of human immunodeficiency virus replication by nonimmunosuppressive analogs of cyclosporin A.
Analogs of the immunosuppressive cyclic undecapeptide cyclosporin A (CsA) with substitutions in positions 1, 4, 6, and/or 11 were rationally designed to possess substantially diminished or no immunosuppressive activity. When these compounds were assayed for their capacity to interfere with the replication of human immunodeficiency virus, some displayed a potent antiviral activity in newly infected cells. However, only CsA could interfere with virus replication in persistently infected cells. One CsA analog with antiviral activity costimulated the phytohemagglutinin-induced production of interleukin 2 by human lymphocytes. Human immunodeficiency virus particles from drug-exposed cells showed lower infectivity than virions from untreated cells. Thus, these nonimmunosuppressive analogs of CsA constitute a promising class of lead compounds to develop drugs for effective treatment of the acquired immunodeficiency syndrome.
Bartz
S R
SR
Department of Medical Microbiology and Immunology, University of Wisconsin, Madison 53706, USA.
Hohenwalter
E
E
Hu
M K
MK
Rich
D H
DH
Malkovsky
M
M
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006678:HIV / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000276:immunology; D008958:Models, Molecular; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D003524:Cyclosporins; D007376:Interleukin-2; D016572:Cyclosporine