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

Abstract

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...

Development and optimization of nanostructured systems loaded with an HIV inhibitory peptide

“…Our group has previously reported a 18-mer linear peptide (namely E1P47), with a broad spectrum activity against HIV-1 and encapsulated it into polymeric nanoparticles (NPs). [2][3][4] In this work, novel PLGA-based mucoadhesive biodegradable NPs were designed to encapsulate E1P47 and enhance its penetration properties through the vaginal mucosa.…”

Stapled peptides as potential inhibitors of SARS‐CoV‐2 binding to the hACE2 receptor

“…optimized HIV-1 fusion inhibitors by applying all-hydrocarbon covalent cross-linking to create so-called "next-generation gp41 HR2 peptides," with markedly increased protease resistance and antiviral activity compared with enfuvirtide. [19] More recently, Gomara et al [20] described the design and synthesis of stapled peptides based on the peptide E1P47, which corresponds to residues 184-201 of the envelope glycoprotein E1 of the human pegivirus, GB virus C (UniProt Q69431_9FLAV). Gomara et al…”

“…Compared with the parent peptide, E1P47, these lactam-stapled peptides showed greater inhibitory potencies in cellular models and inhibited HIV-1 infection in colorectal tissue explants, but they did not show improved resistance to serum proteases. [20] 4 CoV-2 entry process, the reader is referred to recent reviews. [21][22][23]…”

“…More recently, Gomara et al [ 20 ] described the design and synthesis of stapled peptides based on the peptide E1P47, which corresponds to residues 184–201 of the envelope glycoprotein E1 of the human pegivirus, GB virus C (UniProt Q69431_9FLAV). Gomara et al synthesized stapled peptides by lactamization between the amine‐side and carboxy‐side chains of Lys and Asp or Glu amino acid residues.…”

Facile de Novo Sequencing of Tetrazine‐Cyclized Peptides through UV‐Induced Ring‐Opening and Cleavage from the Solid Phase

“…Cyclic peptides are intermediate between small molecules and protein therapeutics in size and physicochemical properties. While linear ligands can adopt various conformations on binding proteins, cyclic peptides, on protein binding, are relatively restricted in their structural geometries [1] . This results in cyclic ligands binding proteins with higher affinities than their linear analogs, [2] as they do not pay the entropic penalty on protein binding.…”