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 journalArticlepeer-review

4 Scopus citations


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
Issue number4
StatePublished - Apr 12 2019

Bibliographical note

Funding Information:
McNaughton lab studies were supported by NIGMS R01GM107520. Harris lab studies were supported by NIAID R37 AI064046. R.S.H. is an Investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2019 American Chemical Society.


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


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