Synthetic Heparanase Inhibitors Can Prevent Herpes Simplex Viral Spread

Pradeep Chopra; Tejabhiram Yadavalli; Francesco Palmieri; Seino A.K. Jongkees; Luca Unione; Deepak Shukla; Geert Jan Boons

doi:10.1002/anie.202309838

Synthetic Heparanase Inhibitors Can Prevent Herpes Simplex Viral Spread

Pradeep Chopra, Tejabhiram Yadavalli, Francesco Palmieri, Seino A.K. Jongkees, Luca Unione, Deepak Shukla^*, Geert Jan Boons^*

^*Corresponding author for this work

University of Illinois at Chicago

Research output: Contribution to journal › Article › Academic

Abstract

Herpes simplex virus (HSV-1) employs heparan sulfate (HS) as receptor for cell attachment and entry. During late-stage infection, the virus induces the upregulation of human heparanase (Hpse) to remove cell surface HS allowing viral spread. We hypothesized that inhibition of Hpse will prevent viral release thereby representing a new therapeutic strategy for HSV-1. A range of HS-oligosaccharides was prepared to examine the importance of chain length and 2-O-sulfation of iduronic moieties for Hpse inhibition. It was found that hexa- and octasaccharides potently inhibited the enzyme and that 2-O-sulfation of iduronic acid is tolerated. Computational studies provided a rationale for the observed structure–activity relationship. Treatment of human corneal epithelial cells (HCEs) infected with HSV-1 with the hexa- and octasaccharide blocked viral induced shedding of HS which significantly reduced spread of virions. The compounds also inhibited migration and proliferation of immortalized HCEs thereby providing additional therapeutic properties.

Original language	English
Article number	e202309838
Number of pages	11
Journal	Angewandte Chemie - International Edition
Volume	62
Issue number	41
DOIs	https://doi.org/10.1002/anie.202309838
Publication status	Published - 9 Oct 2023

Bibliographical note

Funding Information:
This research was supported by the National Institutes of Health (P41GM103390 and HLBI R01HL151617 to G.-J.B.; R01EY029426, R01EY024710, and P30EY001792 to D.S.). We thank Dr. Apoorva Joshi and Dr. Vito Thijssen for technical assistance. We thank Dr. Gideon J. Davies (University of York, York, UK) for providing human heparanase.

Funding Information:
This research was supported by the National Institutes of Health (P41GM103390 and HLBI R01HL151617 to G.‐J.B.; R01EY029426, R01EY024710, and P30EY001792 to D.S.). We thank Dr. Apoorva Joshi and Dr. Vito Thijssen for technical assistance. We thank Dr. Gideon J. Davies (University of York, York, UK) for providing human heparanase.

Publisher Copyright:
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Funding

This research was supported by the National Institutes of Health (P41GM103390 and HLBI R01HL151617 to G.-J.B.; R01EY029426, R01EY024710, and P30EY001792 to D.S.). We thank Dr. Apoorva Joshi and Dr. Vito Thijssen for technical assistance. We thank Dr. Gideon J. Davies (University of York, York, UK) for providing human heparanase. This research was supported by the National Institutes of Health (P41GM103390 and HLBI R01HL151617 to G.‐J.B.; R01EY029426, R01EY024710, and P30EY001792 to D.S.). We thank Dr. Apoorva Joshi and Dr. Vito Thijssen for technical assistance. We thank Dr. Gideon J. Davies (University of York, York, UK) for providing human heparanase.

Funders	Funder number
This research was supported by the National Institutes of Health (P41GM103390 and HLBI R01HL151617 to G.-J.B.; R01EY029426, R01EY024710, and P30EY001792 to D.S.). We thank Dr. Apoorva Joshi and Dr. Vito Thijssen for technical assistance. We thank Dr. Gideo	HLBI R01HL151617, R01EY029426, R01EY024710, P30EY001792
National Institutes of Health
Not added	P41GM103390

Keywords

Antivirals
Drug Discovery
Heparanase
Heparin
Herpes Simplex Virus Type 1

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Angew Chem Int Ed - 2023 - Chopra - Synthetic Heparanase Inhibitors Can Prevent Herpes Simplex Viral SpreadFinal published version, 28 MBLicence: CC BY-NC-ND

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title = "Synthetic Heparanase Inhibitors Can Prevent Herpes Simplex Viral Spread",

abstract = "Herpes simplex virus (HSV-1) employs heparan sulfate (HS) as receptor for cell attachment and entry. During late-stage infection, the virus induces the upregulation of human heparanase (Hpse) to remove cell surface HS allowing viral spread. We hypothesized that inhibition of Hpse will prevent viral release thereby representing a new therapeutic strategy for HSV-1. A range of HS-oligosaccharides was prepared to examine the importance of chain length and 2-O-sulfation of iduronic moieties for Hpse inhibition. It was found that hexa- and octasaccharides potently inhibited the enzyme and that 2-O-sulfation of iduronic acid is tolerated. Computational studies provided a rationale for the observed structure–activity relationship. Treatment of human corneal epithelial cells (HCEs) infected with HSV-1 with the hexa- and octasaccharide blocked viral induced shedding of HS which significantly reduced spread of virions. The compounds also inhibited migration and proliferation of immortalized HCEs thereby providing additional therapeutic properties.",

keywords = "Antivirals, Drug Discovery, Heparanase, Heparin, Herpes Simplex Virus Type 1",

author = "Pradeep Chopra and Tejabhiram Yadavalli and Francesco Palmieri and Jongkees, {Seino A.K.} and Luca Unione and Deepak Shukla and Boons, {Geert Jan}",

note = "Funding Information: This research was supported by the National Institutes of Health (P41GM103390 and HLBI R01HL151617 to G.-J.B.; R01EY029426, R01EY024710, and P30EY001792 to D.S.). We thank Dr. Apoorva Joshi and Dr. Vito Thijssen for technical assistance. We thank Dr. Gideon J. Davies (University of York, York, UK) for providing human heparanase. Funding Information: This research was supported by the National Institutes of Health (P41GM103390 and HLBI R01HL151617 to G.‐J.B.; R01EY029426, R01EY024710, and P30EY001792 to D.S.). We thank Dr. Apoorva Joshi and Dr. Vito Thijssen for technical assistance. We thank Dr. Gideon J. Davies (University of York, York, UK) for providing human heparanase. Publisher Copyright: {\textcopyright} 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.",

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AU - Chopra, Pradeep

AU - Yadavalli, Tejabhiram

AU - Palmieri, Francesco

AU - Jongkees, Seino A.K.

AU - Unione, Luca

AU - Shukla, Deepak

AU - Boons, Geert Jan

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N2 - Herpes simplex virus (HSV-1) employs heparan sulfate (HS) as receptor for cell attachment and entry. During late-stage infection, the virus induces the upregulation of human heparanase (Hpse) to remove cell surface HS allowing viral spread. We hypothesized that inhibition of Hpse will prevent viral release thereby representing a new therapeutic strategy for HSV-1. A range of HS-oligosaccharides was prepared to examine the importance of chain length and 2-O-sulfation of iduronic moieties for Hpse inhibition. It was found that hexa- and octasaccharides potently inhibited the enzyme and that 2-O-sulfation of iduronic acid is tolerated. Computational studies provided a rationale for the observed structure–activity relationship. Treatment of human corneal epithelial cells (HCEs) infected with HSV-1 with the hexa- and octasaccharide blocked viral induced shedding of HS which significantly reduced spread of virions. The compounds also inhibited migration and proliferation of immortalized HCEs thereby providing additional therapeutic properties.

AB - Herpes simplex virus (HSV-1) employs heparan sulfate (HS) as receptor for cell attachment and entry. During late-stage infection, the virus induces the upregulation of human heparanase (Hpse) to remove cell surface HS allowing viral spread. We hypothesized that inhibition of Hpse will prevent viral release thereby representing a new therapeutic strategy for HSV-1. A range of HS-oligosaccharides was prepared to examine the importance of chain length and 2-O-sulfation of iduronic moieties for Hpse inhibition. It was found that hexa- and octasaccharides potently inhibited the enzyme and that 2-O-sulfation of iduronic acid is tolerated. Computational studies provided a rationale for the observed structure–activity relationship. Treatment of human corneal epithelial cells (HCEs) infected with HSV-1 with the hexa- and octasaccharide blocked viral induced shedding of HS which significantly reduced spread of virions. The compounds also inhibited migration and proliferation of immortalized HCEs thereby providing additional therapeutic properties.

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KW - Drug Discovery

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KW - Heparin

KW - Herpes Simplex Virus Type 1

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U2 - 10.1002/anie.202309838

DO - 10.1002/anie.202309838

M3 - Article

AN - SCOPUS:85169814435

SN - 1433-7851

VL - 62

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 41

M1 - e202309838

ER -

Synthetic Heparanase Inhibitors Can Prevent Herpes Simplex Viral Spread

Abstract

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Keywords

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