title: Helix-Grafted Pleckstrin Homology Domains Suppress HIV-1 Infection of CD4-Positive Cells.
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.
authors.affiliation: Department of Chemistry, Colorado State University, Fort Collins, CO, 80523, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Tennyson
authors.affiliation: Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, 80523, USA.
authors.forename: Susanne N
authors.initials: SN
authors.lastname: Walker
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, 55455, USA.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, 55455, USA.|Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota, 55455, USA.
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.affiliation: Department of Chemistry, Colorado State University, Fort Collins, CO, 80523, USA. alan.kennan@colostate.edu.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Kennan
authors.affiliation: Department of Chemistry, Colorado State University, Fort Collins, CO, 80523, USA. brian.mcnaughton@colostate.edu.|Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, 80523, USA. brian.mcnaughton@colostate.edu.
authors.forename: Brian R
authors.initials: BR
authors.lastname: McNaughton
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D006678:HIV / Q000187:drug effects* / Q000502:physiology*; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors / Q000276:immunology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D000070539:Pleckstrin Homology Domains
chemical_list: D015700:HIV Envelope Protein gp41; D008024:Ligands; D010455:Peptides
keywords: CD4-positive; HIV; peptides; pleckstrin homology