Evolved proteins inhibit entry of enfuvirtide-resistant HIV-1

Terumasa Ikeda, Rachel L. Tennyson, Susanne N. Walker, Reuben Harris, Brian R. Mcnaughton

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Drugs that block HIV-1 entry are relatively limited. Enfuvirtide is a 36-residue synthetic peptide that targets gp41 and blocks viral fusion. However, Enfuvirtide-resistant HIV has been reported, and this peptide drug requires daily injection. Previously, we have reported helix-grafted display proteins, consisting of HIV-1 gp41 C-peptide helix grafted onto Pleckstrin Homology domains. Some of these biologics inhibit HIV-1 entry with relatively modest and varied potency (IC50 = 190 nM to >1 μM). Here, we report that gp41 C-peptide helix-grafted Sac7d (Sac7d-Cpep) potently suppresses HIV-1 entry in a live virus assay (IC50 = 1.9-12.4 nM). Yeast display sequence optimization of solvent exposed helix residues led to new biologics with improved expression in E. coli (a common biosimilar expression host), with no appreciable change in entry inhibition. Evolved proteins inhibit the entry of a clinically relevant mutant of HIV-1 that is gp41 C-peptide sensitive and Enfuvirtide resistant. Fusion proteins designed for serum stability also potently suppress HIV-1 entry. Collectively, we report several evolved biologics that are functional against an Enfuvirtide-resistant strain and are designed for serum stability.

Original languageEnglish (US)
Pages (from-to)634-640
Number of pages7
JournalACS Infectious Diseases
Volume5
Issue number4
DOIs
StatePublished - Apr 12 2019

Keywords

  • HIV
  • biologics
  • entry inhibitor
  • protein engineering
  • protein evolution

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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