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Short constrained peptides that inhibit HIV-1 entry.
Samuel K Sia1, Peter A Carr, Andrea G Cochran
1Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge 02142, USA. sia@fas.harvard.edu
Summary
Constraining short HIV C-peptides enhances their ability to block HIV entry by stabilizing their helical structure. This approach improves inhibitory potency, offering new avenues for antiviral drug design.
Area of Science:
- Biochemistry
- Structural Biology
- Virology
Background:
- C-terminal heptad repeat peptides (C-peptides) from HIV-1 gp41 inhibit viral entry.
- Short C-peptides exhibit low binding affinity and poor inhibitory activity against gp41.
- Stabilizing the helical structure of C-peptides is crucial for enhancing inhibitory potency.
Purpose of the Study:
- To improve the inhibitory potency of short C-peptides targeting the gp41 hydrophobic pocket.
- To investigate the utility of chemical crosslinking and unnatural amino acids for stabilizing C-peptide helices.
- To elucidate the thermodynamic basis of C-peptide inhibition.
Main Methods:
- Chemical crosslinking and substitution with unnatural amino acids to stabilize C-peptide helices.
- Assessing cell-cell fusion inhibition and binding affinity to gp41.
- Structural studies and isothermal titration calorimetry (ITC) to analyze binding thermodynamics and helical propensity.
Main Results:
- A constrained peptide (C14linkmid) demonstrated micromolar potency in inhibiting cell-cell fusion.
- Structural studies confirmed binding of constrained peptides to the gp41 hydrophobic pocket.
- Optimal inhibitory potency correlated with a balance in binding enthalpy and entropy, not solely helical propensity.
Conclusions:
- Constraining methods significantly enhance the antiviral activity of short C-peptides.
- The thermodynamic profile of binding is a key determinant of inhibitory efficacy.
- Findings provide a foundation for designing improved constrained peptide inhibitors for HIV.