Herpes Simplex Virus-1 infection in human primary corneal epithelial cells is blocked by a stapled peptide that targets processive DNA synthesis.

Autor: Guan H; Department of Basic and Translational Science, Penn Dental Medicine, USA., Nuth M; Department of Basic and Translational Science, Penn Dental Medicine, USA., Lee V; Scheie Eye Institute, University of Pennsylvania, USA., Lin C; Scheie Eye Institute, University of Pennsylvania, USA., Mitchell CH; Department of Basic and Translational Science, Penn Dental Medicine, USA., Lu W; Department of Basic and Translational Science, Penn Dental Medicine, USA., Scott RW; Fox Chase Chemical Diversity Center, USA., Parker MH; Fox Chase Chemical Diversity Center, USA., Kulp JL 3rd; Fox Chase Chemical Diversity Center, USA., Reitz AB; Fox Chase Chemical Diversity Center, USA., Ricciardi RP; Department of Basic and Translational Science, Penn Dental Medicine, USA. Electronic address: ricciard@upenn.edu.
Jazyk: angličtina
Zdroj: The ocular surface [Ocul Surf] 2021 Jan; Vol. 19, pp. 313-321. Date of Electronic Publication: 2020 Nov 06.
DOI: 10.1016/j.jtos.2020.11.001
Abstrakt: Purpose: Acyclovir is most commonly used for treating ocular Herpes Keratitis, a leading cause of infectious blindness. However, emerging resistance to Acyclovir resulting from mutations in the thymidine kinase gene of Herpes Simplex Virus -1 (HSV-1), has prompted the need for new therapeutics directed against a different viral protein. One novel target is the HSV-1 Processivity Factor which is essential for tethering HSV-1 Polymerase to the viral genome to enable long-chain DNA synthesis.
Methods: A series of peptides, based on the crystal structure of the C-terminus of HSV-1 Polymerase, were constructed with hydrocarbon staples to retain their alpha-helical conformation. The stapled peptides were tested for blocking both HSV-1 DNA synthesis and infection. The most effective peptide was further optimized by replacing its negative N-terminus with two hydrophobic valine residues. This di-valine stapled peptide was tested for inhibiting HSV-1 infection of human primary corneal epithelial cells.
Results: The stapled peptides blocked HSV-1 DNA synthesis and HSV-1 infection. The unstapled control peptide had no inhibitory effects. Specificity of the stapled peptides was confirmed by their inabilities to block infection by an unrelated virus. Significantly, the optimized di-valine stapled peptide effectively blocked HSV-1 infection in human primary corneal epithelial cells with selectivity index of 11.6.
Conclusions: Hydrocarbon stapled peptides that simulate the α-helix from the C-terminus of HSV-1 DNA polymerase can specifically block DNA synthesis and infection of HSV-1 in human primary corneal epithelial cells. These stapled peptides provide a foundation for developing a topical therapeutic for treating human ocular Herpes Keratitis.
(Copyright © 2020. Published by Elsevier Inc.)
Databáze: MEDLINE
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