Peptide Assembly on the Membrane Determines the HIV-1 Inhibitory Activity of Dual-Targeting Fusion Inhibitor Peptides

Gómara, María J.; Pérez, Yolanda; Martinez, Javier P; Barnadas‐Rodríguez, Ramon; Schultz, Anke; Briesen, Hagen von; Perálvarez-Marín, Àlex; Meyerhans, Andreas; Haro, Isabel

doi:10.1038/s41598-019-40125-4

Cited by 10 publications

(20 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, peptide assembly on the membrane as well as recognition of its viral target on the membrane mimetic environment was studied by biophysical assays since it has been demonstrated that fusion inhibitor peptides specifically interfering with the N-terminal region of gp41 21 , need to be embedded into the membrane in order to interact properly with their viral target 22 .…”

Section: Re-e1p47 Assembles Into the Membrane Maintaining The Activementioning

confidence: 99%

“…Once the synthesis of the peptide sequence was completed, a fraction of the peptidyl-resin was labelled at the N-terminus with 5(6)-carboxy-tetramethyl-rhodamine (TAMRA) following the procedure described in Ref. 22 .…”

Section: Synthesis Of Peptidesmentioning

confidence: 99%

“…The identity of the peptides was confirmed by electrospray ionization mass spectrometry (ES-MS) using the equipment and procedure detailed in Ref. 22 . Characterization of RE-E1P47, StP1-E1P47 and StP2-E1P47 is depicted in Figures S7-S9.…”

Section: Synthesis Of Peptidesmentioning

confidence: 99%

“…Changes in the Trp fluorescence spectra were monitored after incubation of 5 µm of each peptide with increasing concentrations of POPC liposomes as described in Ref. 22 . Quenching of Trp by brominated phospholipids was performed using liposomes composed of 1,2-di-(9-10-dibromo) stearoyl-sn-glycero-3-phosphocoline (Br-PC).…”

Section: Synthesis Of Peptidesmentioning

confidence: 99%

“…To get further into the structural features of the most active and proteases-resistant peptide, NMR and computational modelling using the experimental NOE data as distance restrains were addressed. Finally, taking into account that fusion inhibitor peptides specifically interfering with the N-terminal region of gp41 21 need to be embedded into the membrane in order to properly interact with their viral target 22 , we also studied the peptide assembly on the membrane as well as the recognition of its viral target on a membrane mimetic environment.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Importance of structure-based studies for the design of a novel HIV-1 inhibitor peptide

Gómara

Pérez

Gómez-Gutiérrez

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Based on the structure of an HIV-1 entry inhibitor peptide two stapled-and a retro-enantio peptides have been designed to provide novel prevention interventions against HiV transmission. the three peptides show greater inhibitory potencies in cellular and mucosal tissue pre-clinical models than the parent sequence and the retro-enantio shows a strengthened proteolytic stability. Since HIV-1 fusion inhibitor peptides need to be embedded in the membrane to properly interact with their viral target, the structural features were determined by NMR spectroscopy in micelles and solved by using restrained molecular dynamics calculations. Both parent and retro-enantio peptides demonstrate a topology compatible with a shared helix-turn-helix conformation and assemble similarly in the membrane maintaining the active conformation needed for its interaction with the viral target site. This study represents a straightforward approach to design new targeted peptides as HIV-1 fusion inhibitors and lead us to define a retro-enantio peptide as a good candidate for pre-exposure prophylaxis against HIV-1. The therapeutic utility of synthetic peptides as Human Immunodeficiency Virus (HIV) fusion inhibitors is largely limited due to their natural proteogenic structure, which is easily recognized and degraded by proteolytic enzymes. This limitation has hampered the clinical use of T20, a 36-mer peptide that binds to the HIV-1 gp41, and requires high dosing and repeated injections due to its lack of oral bioavailability 1,2. Among the different strategies studied to improve the pharmacokinetic behaviour of peptides composed of natural amino acids, the synthetic d-peptides have demonstrated a higher enzymatic stability, an increased serum half-life and the possibility to be absorbed systemically when taken orally 3,4. d-amino acids decrease the substrate recognition and binding affinity of proteolytic enzymes and confer enzymatic stability to d-peptides 5-7. In addition, it has been recently reported that d-peptides derived from a parent sequence not related to any existing protein silence the immune system and avoid specific humoral responses. Thus retro-D peptides, which display a similar topological arrangement as their parent peptides, offer the advantage of overcoming immunological problems when they are used as therapeutic agents 8. Despite these advantages, a limited number of studies have addressed the therapeutic usefulness of d-peptide structures as HIV-1 fusion inhibitors 9. However, it is worth mentioning 10,11 the cyclic and trimeric d-peptide inhibitors that target the gp41 coiled-coil pocket as well as their subsequent modifications to increase the pharmacokinetics profiles and anti-viral activity 12,13. Alternatively to the use of non-natural amino acids, the introduction of conformational restrictions in linear peptide sequences has been widely used as an strategy to overcome peptide flexibility improving their biological potency 14. Particularly, it has been described the stapling technique which consists on the covalen...

show abstract

Section: Re-e1p47 Assembles Into the Membrane Maintaining The Activementioning

confidence: 99%

Section: Synthesis Of Peptidesmentioning

confidence: 99%

Section: Synthesis Of Peptidesmentioning

confidence: 99%

Section: Synthesis Of Peptidesmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Importance of structure-based studies for the design of a novel HIV-1 inhibitor peptide

Gómara

Pérez

Gómez-Gutiérrez

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

Systematic Evaluation of Fluorination as Modification for Peptide‐Based Fusion Inhibitors against HIV‐1 Infection

et al. 2021

View full text Add to dashboard Cite

With the emergence of novel viruses, the development of new antivirals is more urgent than ever. A key step in human immunodeficiency virus type 1 (HIV-1) infection is six-helix bundle formation within the envelope protein subunit gp41. Selective disruption of bundle formation by peptides has been shown to be effective; however, these drugs, exemplified by T20, are prone to rapid clearance from the patient. The incorporation of non-natural amino acids is known to improve these pharmacokinetic properties. Here, we evaluate a peptide inhibitor in which a critical Ile residue is replaced by fluorinated analogues. We characterized the influence of the fluorinated analogues on the biophysical properties of the peptide. Furthermore, we show that the fluorinated peptides can block HIV-1 infection of target cells at nanomolar levels. These findings demonstrate that fluorinated amino acids are appropriate tools for the development of novel peptide therapeutics.

show abstract

Exploring Viral Interference Using Peptides: Molecular Determinants of HIV‐1 Inhibition by a Peptide Derived from Human Pegivirus‐1 Envelope Protein E2

et al. 2021

View full text Add to dashboard Cite

Co-infection with the human pegivirus 1 (HPgV-1) often has a beneficial effect on disease progression in HIV-1-infected individuals. Several HPgV-1 proteins and peptides, including a 20-mer peptide (P6-2) derived from the N-terminal region of the HPgV-1 surface protein E2, have been associated with this phenomenon, which is referred to as viral interference. We identified the cysteine residues, the hydrophobic core tetrapeptide, as well as the C-terminal negative charge as key factors for the HIV-1 inhibitory activity of P6-2. Analysis of mutations in P6-2-resistant HIV-1 indicated a binding site for the peptide in the HIV-1 envelope glycoprotein gp120. In fact, P6-2 was shown to bind to soluble gp120, as well as to a peptide presenting the gp120 V3 loop. Furthermore, the HIV-1 inhibitory activity of P6-2 could be revoked by the V3 loop peptide, thus indicating a molecular mechanism that involves interaction of P6-2 with the gp120 V3 loop.

show abstract

Peptide Assembly on the Membrane Determines the HIV-1 Inhibitory Activity of Dual-Targeting Fusion Inhibitor Peptides

Cited by 10 publications

References 39 publications

Importance of structure-based studies for the design of a novel HIV-1 inhibitor peptide

Importance of structure-based studies for the design of a novel HIV-1 inhibitor peptide

Systematic Evaluation of Fluorination as Modification for Peptide‐Based Fusion Inhibitors against HIV‐1 Infection

Exploring Viral Interference Using Peptides: Molecular Determinants of HIV‐1 Inhibition by a Peptide Derived from Human Pegivirus‐1 Envelope Protein E2

Contact Info

Product

Resources

About