PD1 CD44 antiviral peptide as an inhibitor of the protein-protein interaction in dengue virus invasion

• Published in: Peptides (New York, N.Y. : 1980) Vol. 153; p. 170797
• Main Authors: Recalde-Reyes, Delia Piedad, Rodríguez-Salazar, Carlos Andrés, Castaño-Osorio, Jhon Carlos, Giraldo, María Isabel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2022
• Subjects: Antiviral agents; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Dengue - drug therapy; Dengue Virus; Envelope; Humans; Hyaluronan receptors; Hyaluronan Receptors - metabolism; Hyaluronan Receptors - therapeutic use; Peptides; Peptides - chemistry; Viral Envelope Proteins - metabolism; C; REU; SCR; BHK; Peptides; NS; E; prM; HS; Dengue virus; Envelope; LPS; PDB; DENV; FBS; HepG2; cDNA; iPPIs; PBS; Antiviral agents; CI; RMSD; NH4Cl; DIOC18; MEM; Hyaluronan receptors; SEM
• ISSN: 0196-9781; 1873-5169; 1873-5169
• DOI: 10.1016/j.peptides.2022.170797

Dengue virus (DENV) infection is mediated by the interaction between the virus envelope protein and cellular receptors of the host cells. In this study, we designed peptides to inhibit protein-protein interaction between dengue virus and CD44 receptor, which is one of the receptors used by DENV for entry. In silico model complexes were designed between domain III of the viral envelope protein of dengue virus 2 and the domain of human CD44 receptor using ClusPro 2.0, (https://cluspro.bu.edu/login.php), and inhibition peptides were designed with Rosetta Online-Server(http://rosie.rosettacommons.org/peptiderive). We identified one linear antiviral peptide of 18 amino acids derived from the human CD44 receptor, PD1 CD44. It did not show hemolysis or toxicity in HepG2 or BHK cell lines, nor did it stimulate the release of IL-1β, IL-6, TNF-α, and IFN-γ, below 100 µM. It had an IC50 of 13.8 µM and maximum effective dose of 54.9 µM evaluated in BHK cells. The decrease in plaque-forming units/mL for DENV1, DENV2, DENV3, and DENV4 was 99.60%, 99.40%, 97.80%, and 70.50%, respectively, and similar results were obtained by RT-qPCR. Non-structural protein 1 release was decreased in pre- and co-treatment but not in post-treatment. Competition assays between the DN59 peptide, envelope protein, and the fragment of domain III "MDKLQLKGMSYSMCTGKF" of the viral envelope of DENV2 and PD1 CD44 showed that our peptide lost its antiviral activity. We demonstrated that our peptide decreased endosome formation, and we propose that it binds to the envelope protein of DENV, inhibiting viral invasion/fusion.
•We identified one lineal antiviral peptide of 18 amino acids derived from the human CD44 receptor, named PD1 CD44.•In vitro assays show peptide PD1 CD44 is safe in eukaryotic cells.•The PD1 CD44 peptide works against 4 serotypes of DENV.•The PD1 CD44 peptide works by inhibition of viral endosome formation in DENV infection.•Assays show PD1 CD44 binds to envelope protein which is highly conserved in DENV and others flavivirus.