Lamellarin α 20-Sulfate, an Inhibitor of HIV-1 Integrase Active against HIV-1 Virus in Cell Culture

Abstract

HIV-1 integrase is an attractive target for anti-retroviral chemotherapy, but to date no clinically useful inhibitors have been developed. We have screened diverse marine natural products for compounds active against integrase in vitro and found a series of ascidian alkaloids, the lamellarins, that show selective inhibition. A new member of the family named lamellarin alpha 20-sulfate (1), the structure of which was determined from spectroscopic data, displayed the most favorable therapeutic index. The site of action of lamellarin alpha 20-sulfate on the integrase protein was mapped by testing activity against deletion mutants of integrase. Inhibition of isolated catalytic domain was detectable though weaker than inhibition of full length integrase; possibly lamellarin alpha 20-sulfate binds a site composed of multiple integrase domains. Lamellarin alpha 20-sulfate also inhibited integration in vitro by authentic HIV-1 replication intermediates isolated from infected cells. Lamellarin alpha 20-sulfate was tested against wild type HIV using the MAGI indicator cell assay and found to inhibit early steps of HIV replication. To clarify the inhibitor target, we tested inhibition against an HIV-based retroviral vector bearing a different viral envelope. Inhibition was observed, indicating that the HIV envelope cannot be the sole target of lamellarin alpha 20-sulfate in cell culture. In addition, these single round tests rule out action against viral assembly or budding. These findings provide a new class of compounds for potential development of clinically useful integrase inhibitors.

A New Class of HIV-1 Integrase Inhibitors: The 3,3,3‘,3‘-Tetramethyl-1,1‘-spirobi(indan)-5,5‘,6,6‘-tetrol Family

“…Similar to previous work that identified a number of sulfated marine natural products 15,68,102 and sulfated synthetic molecules 11,45,54 as IN inhibitors, we observed that three of the four sulfated molecules (16)(17)(18) were inhibitors. Specifically, they were more active than the parent hydroxyl compounds (1, 8, and 11).…”

Specific Inhibition of Human Immunodeficiency Virus Type 1 (HIV-1) Integration in Cell Culture: Putative Inhibitors of HIV-1 Integrase

“…Recently, a number of compounds identified in cell-free assays have been shown to inhibit viral replication in cell culture without displaying significant cytotoxicity (15,26,31,39,44,45,49,50). AR177 (a G-quartet-containing oligonucleotide that forms highly stable intermolecular tetrad structures) and members of the bisaroyl hydrazine family of integrase inhibitors have been shown to inhibit in vitro integration reactions in the nanomolar and low micromolar ranges respectively (6, 37; N. Neamati et al, submitted for publication).…”

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

“…in 1985 [42]. They were later extracted from various ascidians belonging to the Didemnum genus [43][44][45][46][47][48] and in some sponges [49,50] collected from widely varying locations, which suggests a potential microbial link to their biosynthesis.…”