Anti-human immunodeficiency virus activity of novel aminoglycoside-arginine conjugates at early stages of infection.
Conjugates of L-arginine with aminoglycosides have already been described as potent in vitro inhibitors of the HIV-1 Tat-trans-activation responsive element interaction. The polycationic nature of these agents leads us to suggest that they may be active against HIV-1 replication by inhibiting earlier stages of the virus life cycle. We have found that R4K and R3G, kanamycin A, and gentamicin C, conjugated with arginine, inhibited HIV-1 NL4-3 replication at EC50 values of 15 and 30 microM for R3G and R4K, respectively, without a detectable tonic effect on MT-4 cells at concentrations higher than 4000 and about 1000 microM, respectively. Both compounds inhibited the binding of a monoclonal antibody (12G5) directed to CXCR4 as well as the intracellular Ca2+ signal induced by the chemokine SDF-1alpha on CXCR4+ cells, suggesting that aminoglycoside-arginine conjugates interact with CXCR4, the coreceptor used by T-tropic, X4 strains of HIV-1. On the other hand, CB4K, a conjugate of kanamycin A with gamma-guanidinobutyric acid, structurally similar to R4K, failed to display any anti-HIV activity of CXCR4 antagonist activity. An HIV-1 strain that was made resistant to the known CXCR4 antagonist AMD3100 was cross-resistant to both R4K and R3G. However, unlike SDF-1alpha and R4K, R3G inhibited the binding of HIV-1 to MT-4 cells. Aminoglycoside-arginine conjugates inhibit HIV replication by interrupting the early phase of the virus life cycle, namely virus binding to CD4 cells and interaction with CXCR4. R3G and R4K may serve as prototypes of novel anti-HIV agents and should be further studied.
Cabrera
C
C
Institut de Recerca de la SIDA-Caixa (irsiCaixa), Retrovirology Laboratory, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
Gutiérrez
A
A
Blanco
J
J
Barretina
J
J
Litovchick
A
A
Lapidot
A
A
Evdokimov
A G
AG
Clotet
B
B
Esté
J A
JA
D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000911:Antibodies, Monoclonal; D001120:Arginine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001596:Benzylamines; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000080027:Cyclams; D005434:Flow Cytometry; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007612:Kanamycin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; C411972:R3G conjugate; C411970:R4K conjugate; D019718:Receptors, CXCR4; D007612:Kanamycin; D001120:Arginine; C088327:plerixafor