Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy.
The introduction of highly active antiretroviral therapy (HAART) has significantly decreased morbidity and mortality among patients infected with HIV-1. However, HIV-1 can acquire resistance against all currently available antiretroviral drugs targeting viral reverse transcriptase, protease, and gp41. Moreover, in a growing number of patients, the development of multidrug-resistant viruses compromises HAART efficacy and limits therapeutic options. Therefore, it is an ongoing task to develop new drugs and to identify new targets for antiretroviral therapy. Here, we identified the guanylhydrazone CNI-1493 as an efficient inhibitor of human deoxyhypusine synthase (DHS). By inhibiting DHS, this compound suppresses hypusine formation and, thereby, activation of eukaryotic initiation factor 5A (eIF-5A), a cellular cofactor of the HIV-1 Rev regulatory protein. We demonstrate that inhibition of DHS by CNI-1493 or RNA interference efficiently suppressed the retroviral replication cycle in cell culture and primary cells. We show that CNI-1493 inhibits replication of macrophage- and T cell-tropic laboratory strains, clinical isolates, and viral strains with high-level resistance to inhibitors of viral protease and reverse transcriptase. Moreover, no measurable drug-induced adverse effects on cell cycle transition, apoptosis, and general cytotoxicity were observed. Therefore, human DHS represents a novel and promising drug target for the development of advanced antiretroviral therapies, particularly for the inhibition of multidrug-resistant viruses.
Hauber
Ilona
I
Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg, Germany.
Bevec
Dorian
D
Heukeshoven
Jochen
J
Krätzer
Friedrich
F
Horn
Florian
F
Choidas
Axel
A
Harrer
Thomas
T
Hauber
Joachim
J
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D018432:Drug Resistance, Multiple; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015694:Gene Products, rev / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D015533:Transcriptional Activation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D054321:rev Gene Products, Human Immunodeficiency Virus; D000813:Anilides; D006146:Guanidines
D019380:Anti-HIV Agents; D015694:Gene Products, rev; D006835:Hydrazones; D008239:Lysine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D054321:rev Gene Products, Human Immunodeficiency Virus; C100028:hypusine; C097256:semapimod; D000813:Anilides; D006146:Guanidines; C063507:deoxyhypusine synthase