Basic residues are critical to the activity of peptide inhibitors of human T cell leukemia virus type 1 entry.
A synthetic peptide based on the leash and alpha-helical region (LHR) of human T cell leukemia virus type 1 envelope is a potent inhibitor of viral entry into cells. The inhibitory peptide targets a triple-stranded coiled-coil motif of the fusion-active transmembrane glycoprotein and in a trans-dominant negative manner blocks resolution to the trimer-of-hairpins form. The LHR-mimetic is, therefore, functionally analogous to the C34/T20-type inhibitors of human immunodeficiency virus. Previous attempts to shorten the bioactive peptide produced peptides with severely attenuated activity. We now demonstrate that truncated peptides often suffer from poor solubility and impaired coiled coil binding properties, and we identify features that are critical to peptide function. In particular, the alpha-helical region of the LHR-mimetic is necessary but not sufficient for inhibitory activity. Moreover, two basic residues are crucial for coiled-coil binding and efficient inhibition of membrane fusion. By retaining these basic residues and a region of main chain peptide contacts with the coiled coil, a core LHR-mimetic was obtained that retains both the inhibitory properties and solubility profile of the parental peptide. Variants of the core peptide inhibit both membrane fusion and infection of cells by free viral particles, but unexpectedly, infection by virions was more susceptible to inhibition by low activity inhibitors than syncytium formation. The core inhibitor provides a valuable lead in the search for smaller more bio-available peptides and peptido-mimetics that possess anti-viral activity. Such molecules may be attractive candidates for therapeutic intervention in human T cell leukemia virus type 1 infections.
Lamb
Daniel
D
Biomedical Research Centre, Ninewells Hospital and Medical School, The University, Dundee DD1 9SY, Scotland, United Kingdom.
Mirsaliotis
Antonis
A
Kelly
Sharon M
SM
Brighty
David W
DW
D020816:Amino Acid Motifs; D044966:Anti-Retroviral Agents / Q000737:chemistry / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology*; D015490:HTLV-I Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects*
D044966:Anti-Retroviral Agents; D010455:Peptides; D014759:Viral Envelope Proteins