Characterization of the effects of two polysulfonated distamycin A derivatives, PNU145156E and PNU153429, on HIV type 1 Tat protein.
We examined whether two sulfonated distamycin A derivatives, PNU145156E and PNU153529, inhibit the trans-activating and angiogenic effects of HIV-1 Tat protein. The study was carried out by analyzing the activity of the two drugs on: (1) extracellular and intracellular Tat protein, introduced into HL3T1 cells containing an integrated HIV-1 LTR/CAT plasmid; (2) binding of Tat to 3H-labeled heparin and to 14C-labeled PNU145156E; and (3) the angiogenic response induced in vivo by culture medium conditioned by T53c14 cells, which release extracellular Tat. PNU145156E and PNU153429 interacted with extracellular Tat in the culture medium and physically bound the Tat protein, most likely sequestering it in the extracellular space. As a consequence, the two drugs inhibited trans-activation of the HIV-1 LTR on addition of the free Tat protein to HL3T1 cells. However, the two compounds inhibited the activity of intracellular Tat when they were introduced into the cells by lipofection. In vivo experiments showed that the two drugs blocked the neoangiogenesis induced by Tat released in the conditioned medium of T53c14 cells. Owing to the critical role of intracellular and extracellular Tat in HIV-1 replication, these drugs show promise as a means to control the progression of HIV-1 infection as well as the neoplastic and angiogenic effects induced by Tat in the course of AIDS.
Corallini
A
A
Department of Experimental and Diagnostic Medicine, and the Interdepartment Centre for Biotechnology, University of Ferrara, Italy.
Betti
M
M
Rusnati
M
M
Campioni
D
D
Ciomei
M
M
Sola
F
F
Calza
N
N
Zauli
G
G
Presta
M
M
Barbanti-Brodano
G
G
Caputo
A
A
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004214:Distamycins / Q000494:pharmacology*; D005260:Female; D015696:Gene Products, tat / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D015497:HIV-1; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D009389:Neovascularization, Pathologic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013431:Sulfates; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D054322:tat Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D004214:Distamycins; C085720:FCE 26644; D015696:Gene Products, tat; C113015:PNU 153429; D011993:Recombinant Fusion Proteins; D013431:Sulfates; D054322:tat Gene Products, Human Immunodeficiency Virus; D005982:Glutathione Transferase