Bloom Pilot Project Summary

The continual threat of resistance to HIV-1 treatments has fueled a need for developing new classes of antiretroviral inhibitors with novel mechanisms of action.i Antiretrovirals which target the HIV nucleocapsid (NC) protein have gained particular interests in recent years.ii NC is an essential protein involved in the recognition and packaging of viral RNA and the onset of early stage HIV infection. Disruption of NC function herefore provides a unique opportunity to arrest HIV viral replication at several points in the viral life cycle and to halt the progression of HIV infection altogether. Nevertheless, the highly flexible nature, high basicity, and the presence of zinc-coordinating zinc fingers have made NC a difficult target for traditional small molecule-based therapeutics.2 Synthetic peptides containing non-proteinogenic amino acids (NPAAs) represent an attractive alternative to small molecules for targeting complex proteins like NC.iii Despite this fact, the discovery of an NPAA-containing peptide inhibitor for NC has yet to occur. In 2008, Dietrich reported a short peptide sequence, His-Trp-Trp-Pro-Trp-Trp, which halted HIV-1 infectivity by competitively blocking the interaction between NC and y-RNA.iv Unfortunately, this peptide also displayed poor metabolic stability and bioavailability. As the incorporation of NPAAs into native peptides can enhance their receptor potency, selectivity, and metabolically stability, it stands to reason that the introduction of NPAAs into the Dietrich sequence could vastly improve its therapeutic potential in route to a new clinical candidate for HIV-1.

We propose here the use of a novel donor-acceptor platform to accelerate the discovery of an optimal NPAA-variant of the Dietrich sequence. In our approach, a single precursor peptide harboring a single dehydroalanine (Dha) "acceptor residue" in a defined position is made using standard solid phase peptide synthesis (SPPS). Then, visible light and a flavin photocatalyst are used to transfer the desired NPAA side chain to the Dha acceptor residue from a "donor" boronic acid. In this way, the product of a single SPPS procedure can be the progenitor of a multitude of peptides, each containing a different NPAA, at a defined location, in just one step per peptide. This strategy will enable NPAA-containing variants of the Dietrich sequence to be rapidly assembled and biologically evaluated.

Project Title

  • Illuminating Old Catalysts for the Synthesis of Anti-Infective HIV Peptides

Project Investigator

  • Steven Bloom, Assistant Professor, Dept. of Medicinal Chemistry, University of Kansas