Peptide Amphiphilic-Based Supramolecular Structures with Anti-HIV-1 Activity.

Maria J Gómara,Isabel Haro,Paul Ziprin,Carolina Herrera,Ramon Pons

doi:10.1021/acs.bioconjchem.1c00292

Maria J Gómara, Isabel Haro + Show 3 more

Open Access

https://doi.org/10.1021/acs.bioconjchem.1c00292

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Abstract

In a previous work, we defined a novel HIV-1 fusion inhibitor peptide (E1P47) with a broad spectrum of activity against viruses from different clades, subtypes, and tropisms. With the aim to enhance its efficacy, in the present work we address the design and synthesis of several peptide amphiphiles (PAs) based on the E1P47 peptide sequence to target the lipid rafts of the cell membrane where the cell–cell fusion process takes place. We report the synthesis of novel PAs having a hydrophobic moiety covalently attached to the peptide sequence through a hydrophilic spacer of polyethylene glycol. Characterization of self-assembly in condensed phase and aqueous solution as well as their interaction with model membranes was analyzed by several biophysical methods. Our results demonstrated that the length of the spacer of polyethylene glycol, the position of the peptide conjugation as well as the type of the hydrophobic residue determine the antiviral activity of the construct. Peptide amphiphiles with one alkyl tail either in C-terminus (C-PAmonoalkyl) or in N-terminus (N-PAmonoalkyl) showed the highest anti-HIV-1 activities in the cellular model of TZM-bl cells or in a preclinical model of the human mucosal tissue explants.

Highlights

Fusion/entry inhibitors are considered promising antiviral agents because they can prevent the transmission of enveloped viruses by inhibiting the viral entry into the host cell.[1]
Taking into account that the HIV-1 envelope glycoprotein is located in lipid rafts during the process of viral fusion and that these subdomains of the plasma membrane contain 3- to 5-fold the amount of cholesterol found in the surrounding bilayer,[23] we have obtained E1P47 derivatives containing cholesterol within its primary structure
The Fmoc-PEGXCOOH derivatives (PEG3 or PEG27) as well as N-succinyloctadecylamine or N-succinyl-dioctadecylamine were stepwise coupled on the solid phase to the N-terminus of the E1P47 the peptide sequence and the hydrophobic tails to obtain the novel peptide amphiphiles (PAs)

Summary

■ INTRODUCTION

Fusion/entry inhibitors are considered promising antiviral agents because they can prevent the transmission of enveloped viruses by inhibiting the viral entry into the host cell.[1]. In the last 30 years, HIV has been one of the most studied enveloped viruses, and it has been taken as a study model in the development of peptide-based fusion/entry inhibitors.[7,8] the 36-mer peptide, T20 or Enfuvirtide, has been the first peptide-based entry inhibitor approved by the FDA for clinical use in HIV-infected patients.[9] In contrast to the already mentioned advantages offered by peptide-based entry inhibitors, such as high specificity and safety, one of the major drawbacks of this type of molecules is its susceptibility to proteolytic degradation, having shorter half-life in vivo as well as lack of oral bioavailability With this in mind, optimization of both sequence and structure of peptide-based inhibitors has been carried out in order to prolong their halflife, increase their antiviral activity, and improve druggability. AThe IC values shown are the means (SEM) derived from the triplicates for each condition performed

■ RESULTS

■ DISCUSSION

■ ACKNOWLEDGMENTS

■ REFERENCES