A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats.
The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1(IIIB) and HIV-1(BaL) as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1(IIIB) activity, whereas fusion inhibitors showed both anti-HIV-1(IIIB) and anti-HIV-1(BaL) activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, "phenotypic drug evaluation", may be applicable for the evaluation of various antiviral drugs in vivo.
Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575, Japan.
Xiaoguang
X
Li
Hua
H
Qian
Fusako
F
Miyamoto
Takeshi
T
Naito
Kumi
K
Kawaji
Kazumi
K
Kajiwara
Toshio
T
Hattori
Masao
M
Matsuoka
Kentaro
K
Watanabe
Shinya
S
Oishi
Nobutaka
N
Fujii
Eiichi N
EN
Kodama
D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001682:Biological Availability; D004353:Drug Evaluation, Preclinical; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000008:administration & dosage; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D007700:Kinetics; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage; D010455:Peptides / Q000008:administration & dosage; D010456:Peptides, Cyclic / Q000008:administration & dosage; D051381:Rats; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D013997:Time Factors; D053586:Virus Internalization / Q000187:drug effects
D019380:Anti-HIV Agents; C486264:Cxcr4 protein, rat; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D010455:Peptides; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4; C540660:SC29EK peptide; C496951:cyclo(tyrosyl-arginyl-arginyl-3-(2-naphthyl)alanyl-glycyl); D000077560:Enfuvirtide