Preclinical evaluation of a zinc finger inhibitor targeting lentivirus nucleocapsid protein in SIV-infected monkeys.
There is a continued need to develop inexpensive and effective drugs specific for novel targets of human immunodeficiency virus type 1 (HIV-1). The HIV-1 nucleocapsid p7 (NCp7) protein plays a critical role in early and late stages of the virus life cycle and possesses two highly conserved retroviral zinc fingers that are essential for its function. We have previously shown that zinc finger inhibitors (ZFI) based on the S-acyl 2-mercaptobenzamide thioester (SAMT) chemotype specifically target HIV NCp7 and are effective at reducing levels of infectious virus in an HIV-1-transgenic mouse model. Here, we did an initial proof-of-concept study to test the potential of a lead SAMT compound to reduce virus infectivity in the simian immunodeficiency virus (SIV) nonhuman primate model. SAMT-19 had potent antiviral and virucidal effects against the primary pathogenic isolate SIV/DeltaB670 and was non-cytotoxic in vitro. Cynomolgus macaques were infected intrarectally with SIV/DeltaB670 and treated with a low dose of SAMT-19 by continuous infusion from day 8 to day 28 post infection. Monkeys in the treatment group had significantly lower levels of infectious virus in peripheral blood mononuclear cells during the course of therapy as compared to monkeys in the control group, although therapy had no demonstrable effect on virus load. SAMT-19 therapy did not alter liver, kidney or immunologic function and was well tolerated by all treated monkeys. These data demonstrate that SAMT-19 is safe and virucidal in the nonhuman primate model. Further studies directed at optimizing SAMT bioavailability and pharmacokinetics likely will result in enhanced therapeutic efficacy of this promising HIV therapeutic.
Schito
Marco L
ML
Laboratory of Cell Biology, National Cancer Institute, National Institute of Health, Bethesda, Maryland 20892, USA. schitom@mail.nih.gov
Soloff
Adam C
AC
Slovitz
Danielle
D
Trichel
Anita
A
Inman
John K
JK
Appella
Ettore
E
Turpin
Jim A
JA
Barratt-Boyes
Simon M
SM
D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D036022:Capsid Proteins / Q000037:antagonists & inhibitors*; D015683:Gene Products, gag / Q000037:antagonists & inhibitors*; D007963:Leukocytes, Mononuclear / Q000821:virology; D008252:Macaca fascicularis; D008297:Male; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D016335:Zinc Fingers / Q000187:drug effects*; D054301:gag Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D036022:Capsid Proteins; D015683:Gene Products, gag; C071884:NCP7 protein, Human immunodeficiency virus 1; D013438:Sulfhydryl Compounds; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus