Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner (2024)

Sun, L., Chopra, P., Tomris, I., van der Woude, R., Liu, L., de Vries, R. P. (2023). Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner. JACS Au, 3(4), 1185-1195. https://doi.org/10.1021/jacsau.3c00042

Sun, Lifeng ; Chopra, Pradeep ; Tomris, Ilhan et al. / Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner. In: JACS Au. 2023 ; Vol. 3, No. 4. pp. 1185-1195.

@article{6f308e6f21a6409eb319cf324f647dee,

title = "Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner",

abstract = "The emergence of new SARS-CoV-2 variants and the dangers of long-covid necessitate the development of broad-acting therapeutics that can reduce viral burden. SARS-CoV-2 employs heparan sulfate (HS) as an initial cellular attachment factor, and therefore, there is interest in developing heparin as a therapeutic for SARS-CoV-2. Its use is, however, complicated by structural heterogeneity and the risk of causing bleeding and thrombocytopenia. Here, we describe the preparation of well-defined heparin mimetics by a controlled head-to-tail assembly of HS oligosaccharides having an alkyne or azide moiety by copper-catalyzed azide-alkyne cycloaddition (CuAAC). Alkyne- and azide-containing sulfated oligosaccharides were prepared from a common precursor by modifying an anomeric linker with 4-pentynoic acid and by enzymatic extension with an N-acetyl-glucosamine having an azide moiety at C-6 (GlcNAc6N 3), respectively, followed by CuAAC. The process of enzymatic extension with GlcNAc6N 3 followed by CuAAC with the desired alkyne-containing oligosaccharides could be repeated to give compounds composed of 20 and 27 monosaccharides, respectively. The heparin mimetics could inhibit the binding of the SARS-CoV-2 spike or RBD to immobilized heparin or to Vero E6 cells. The inhibitory potency increased with increasing chain length, and a compound composed of four sulfated hexasaccharides linked by triazoles had a similar potency as unfractionated heparin. Sequence analysis and HS microarray binding studies with a wide range of RBDs of variants of concern indicate that they have maintained HS-binding capabilities and selectivities. The heparin mimetics exhibit no or reduced binding to antithrombin-III and platelet factor 4, respectively, which are associated with side effects. ",

keywords = "chemoenzymatic synthesis, coronavirus, glyco-mimetics, glycosyl transferases, multivalent",

author = "Lifeng Sun and Pradeep Chopra and Ilhan Tomris and {van der Woude}, Roosmarijn and Lin Liu and {de Vries}, {Robert P.} and Boons, {Geert Jan}",

note = "Funding Information: This research was supported by the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme (Grant 899687 (HS-SEQ) to G.J.B.), the Chinese Scholarship Council (to L.S.), and the European Commission (ERC Starting Grant 802780 to R.P.d.V.). Gerlof P. Bosman expressed the enzyme PmHS2. Publisher Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society.",

year = "2023",

month = apr,

day = "24",

doi = "10.1021/jacsau.3c00042",

language = "English",

volume = "3",

pages = "1185--1195",

journal = "JACS Au",

issn = "2691-3704",

publisher = "American Chemical Society",

number = "4",

}

Sun, L, Chopra, P, Tomris, I, van der Woude, R, Liu, L, de Vries, RP 2023, 'Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner', JACS Au, vol. 3, no. 4, pp. 1185-1195. https://doi.org/10.1021/jacsau.3c00042

Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner. / Sun, Lifeng; Chopra, Pradeep; Tomris, Ilhan et al.
In: JACS Au, Vol. 3, No. 4, 24.04.2023, p. 1185-1195.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner

AU - Sun, Lifeng

AU - Chopra, Pradeep

AU - Tomris, Ilhan

AU - van der Woude, Roosmarijn

AU - Liu, Lin

AU - de Vries, Robert P.

AU - Boons, Geert Jan

N1 - Funding Information:This research was supported by the European Union’s Horizon 2020 Research and Innovation Programme (Grant 899687 (HS-SEQ) to G.J.B.), the Chinese Scholarship Council (to L.S.), and the European Commission (ERC Starting Grant 802780 to R.P.d.V.). Gerlof P. Bosman expressed the enzyme PmHS2.Publisher Copyright:© 2023 The Authors. Published by American Chemical Society.

PY - 2023/4/24

Y1 - 2023/4/24

N2 - The emergence of new SARS-CoV-2 variants and the dangers of long-covid necessitate the development of broad-acting therapeutics that can reduce viral burden. SARS-CoV-2 employs heparan sulfate (HS) as an initial cellular attachment factor, and therefore, there is interest in developing heparin as a therapeutic for SARS-CoV-2. Its use is, however, complicated by structural heterogeneity and the risk of causing bleeding and thrombocytopenia. Here, we describe the preparation of well-defined heparin mimetics by a controlled head-to-tail assembly of HS oligosaccharides having an alkyne or azide moiety by copper-catalyzed azide-alkyne cycloaddition (CuAAC). Alkyne- and azide-containing sulfated oligosaccharides were prepared from a common precursor by modifying an anomeric linker with 4-pentynoic acid and by enzymatic extension with an N-acetyl-glucosamine having an azide moiety at C-6 (GlcNAc6N 3), respectively, followed by CuAAC. The process of enzymatic extension with GlcNAc6N 3 followed by CuAAC with the desired alkyne-containing oligosaccharides could be repeated to give compounds composed of 20 and 27 monosaccharides, respectively. The heparin mimetics could inhibit the binding of the SARS-CoV-2 spike or RBD to immobilized heparin or to Vero E6 cells. The inhibitory potency increased with increasing chain length, and a compound composed of four sulfated hexasaccharides linked by triazoles had a similar potency as unfractionated heparin. Sequence analysis and HS microarray binding studies with a wide range of RBDs of variants of concern indicate that they have maintained HS-binding capabilities and selectivities. The heparin mimetics exhibit no or reduced binding to antithrombin-III and platelet factor 4, respectively, which are associated with side effects.

AB - The emergence of new SARS-CoV-2 variants and the dangers of long-covid necessitate the development of broad-acting therapeutics that can reduce viral burden. SARS-CoV-2 employs heparan sulfate (HS) as an initial cellular attachment factor, and therefore, there is interest in developing heparin as a therapeutic for SARS-CoV-2. Its use is, however, complicated by structural heterogeneity and the risk of causing bleeding and thrombocytopenia. Here, we describe the preparation of well-defined heparin mimetics by a controlled head-to-tail assembly of HS oligosaccharides having an alkyne or azide moiety by copper-catalyzed azide-alkyne cycloaddition (CuAAC). Alkyne- and azide-containing sulfated oligosaccharides were prepared from a common precursor by modifying an anomeric linker with 4-pentynoic acid and by enzymatic extension with an N-acetyl-glucosamine having an azide moiety at C-6 (GlcNAc6N 3), respectively, followed by CuAAC. The process of enzymatic extension with GlcNAc6N 3 followed by CuAAC with the desired alkyne-containing oligosaccharides could be repeated to give compounds composed of 20 and 27 monosaccharides, respectively. The heparin mimetics could inhibit the binding of the SARS-CoV-2 spike or RBD to immobilized heparin or to Vero E6 cells. The inhibitory potency increased with increasing chain length, and a compound composed of four sulfated hexasaccharides linked by triazoles had a similar potency as unfractionated heparin. Sequence analysis and HS microarray binding studies with a wide range of RBDs of variants of concern indicate that they have maintained HS-binding capabilities and selectivities. The heparin mimetics exhibit no or reduced binding to antithrombin-III and platelet factor 4, respectively, which are associated with side effects.

KW - chemoenzymatic synthesis

KW - coronavirus

KW - glyco-mimetics

KW - glycosyl transferases

KW - multivalent

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U2 - 10.1021/jacsau.3c00042

DO - 10.1021/jacsau.3c00042

M3 - Article

C2 - 37101566

AN - SCOPUS:85152208648

SN - 2691-3704

VL - 3

SP - 1185

EP - 1195

JO - JACS Au

JF - JACS Au

IS - 4

ER -

Sun L, Chopra P, Tomris I, van der Woude R, Liu L, de Vries RP et al. Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner. JACS Au. 2023 Apr 24;3(4):1185-1195. doi: 10.1021/jacsau.3c00042