Three Distinct Host Assembly Machine-Targeted Small Molecules with Unexpected Implications for HIV Cure
Prosetta’s application of its unique cell free protein synthesis platform to the assembly of HIV capsids is an example of how the discovery of new biochemical pathways creates the possibility of new treatments for complex diseases. HIV is one of the most complex disease challenges humans have yet faced. Despite remarkable progress in converting HIV from a short term death sentence to a manageable chronic disease, a cure remains elusive. Fresh approaches and new pathways to target HIV would be extremely useful.
The host-catalyzed HIV assembly pathway discovered and being interrogated by Prosetta is precisely such a completely new concept, and has the promise to match. With multiple steps, each likely catalyzed by a different HIV-specific aberrant assembly machine, it is ripe with possibilities that may be useful in the search for a cure.
Prosetta has discovered three novel mechanisms by which chemotypes from its Hitfinder collection act during HIV infection. Each appears to involve a different assembly machine with distinctive properties. One appears to direct the HIV gag protein to a non-ubitquitin-mediated proteasomal pathway of degradation, suggesting a novel means of augmenting MHC class I presentation to repair the T cell deficit typically associated with long-term HIV. A second chemotype results in release of non-infectious viral particles due to aberrant capsid formation, with no effect on the proteolytic maturation of HIV proteins that accompanies normal capsid assembly (cleavage of p55 to p24). As has been empirically observed in Prosetta’s rabies animal trial, these non-infectious particles represent novel vaccine candidates with the potential to elicit broadly neutralizing antibodies, perhaps due to presentation of epitopes normally masked in mature HIV.
Finally, Prosetta has discovered several chemotypes with the unusual property of displaying all of their anti-HIV activity after the virus has entered the cell but before there is any expression of viral genes. This is consistent with catalyzed disassembly by the cell of the capsid of the first infecting viral particle. Because it would block HIV prior to its integration into the genome - the basis for establishing the chronically infected state - inhibiting the responsible (dis)assembly machine represents a completely novel means of preventing the re-infection of already cleared compartments, removing a major obstacle to a cure.
With further advancement, it is possible that these three drugs, alone or in combination, will make an essential contribution to a long awaited cure for HIV. Prosetta pursues funding and partnerships to do so.