Back when I started teaching virology – 1981 it was, so I’ve been doing it for 30 years come January! – there were precious few agents that did anything to viruses, apart from antibodies and that wonderful new and precious stuff called interferon. Oh, and nucleoside analogues like adenine arabinoside (araA), ribavirin, and the legendary amantadine and rimantidine – which pretty much only covered herpes- and influenza viruses, according to Fenner and White’s Medical Virology of 1986.
And then along came HIV….and everything changed.
All of a sudden, we have an embarrassment of riches – against retroviruses, anyway. Consider the following:
- Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI) inhibit reverse transcription
- Non-nucleoside reverse transcriptase inhibitors (NNRTI)
- Protease inhibitors (PIs) target viral assembly
- Integrase inhibitors inhibit integration of viral DNA into the DNA of the infected cell
- Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets.
- Maturation inhibitors inhibit the last step in gag processing in which the viral capsid polyprotein is cleaved
Of course the above serve to vindicate most thoroughly my “Entrance, Entertainment and Exit” mantra / mnemonic for virus replication, in that they block entrance, interfere with entertainment (replication), and mess with exit too.
But wait, there’s more: a brand-new paper in PLoS Pathogens describes the wide-spectrum anti HIV-1 and -2 activity of a new class of small molecule antiretroviral compounds. These directly target HIV-1 capsid (CA; p24 protein) via binding into a “pocket” in the N-terminus, and thereby interfere with both assembly and uncoating of virions.
HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention.
Blair WS, Pickford C, Irving SL, Brown DG, Anderson M, et al. (2010)
PLoS Pathog 6(12): e1001220. doi:10.1371/journal.ppat.1001220 Published December 9, 2010
Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.
So, yet another target in HIV for chemotherapeutic agents – but what, exactly, are these new magic bullets?
And in Figure 5 of the original paper, you can see what it is that they do:
a) Overlays of capsid structures with PF-3450074 in blue and CAP-1 in pink bound to capsid N-terminal domain; b) Close up view of PF-3450074 site (binding site residues labelled in black, R1-3 sub-pockets labelled in purple)…. c) Location of resistant mutations (purple) in relation to PF-3450074 capsid binding site.
The authors conclude their article with this:
The broad spectrum activity of this series [of drugs] is particularly exciting and highlights this novel mechanism [binding the CA protein] as a significant therapeutic opportunity.
Definitely not an over-stated conclusion! And nicely rounding out a recent series of HIV-combatting articles and developments covered here recently. And let me also refer you here to AJ Cann’s most recent post, on HIV entry – which, surprisingly, is still not a nailed-down and simple model. And which I discovered literally while writing this, so seriously hot off the press.