Helix-Grafted Pleckstrin Homology Domains Suppress HIV-1 Infection of CD4-Positive Cells

Rachel L. Tennyson, Susanne N. Walker, Terumasa Ikeda, Reuben S. Harris, Alan J. Kennan, Brian R. McNaughton

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The size, functional group diversity and three-dimensional structure of proteins often allow these biomolecules to bind disease-relevant structures that challenge or evade small-molecule discovery. Additionally, folded proteins are often much more stable in biologically relevant environments compared to their peptide counterparts. We recently showed that helix-grafted display—extensive resurfacing and elongation of an existing solvent-exposed helix in a pleckstrin homology (PH) domain—led to a new protein that binds a surrogate of HIV-1 gp41, a validated target for inhibition of HIV-1 entry. Expanding on this work, we prepared a number of human-derived helix-grafted-display PH domains of varied helix length and measured properties relevant to therapeutic and basic research applications. In particular, we showed that some of these new reagents expressed well as recombinant proteins in Escherichia coli, were relatively stable in human serum, bound a mimic of pre-fusogenic HIV-1 gp41 in vitro and in complex biological environments, and significantly lowered the incidence of HIV-1 infection of CD4-positive cells.

Original languageEnglish (US)
Pages (from-to)1945-1950
Number of pages6
JournalChemBioChem
Volume17
Issue number20
DOIs
StatePublished - Oct 17 2016

Keywords

  • CD4-positive
  • HIV
  • peptides
  • pleckstrin homology

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