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. 2018 Aug 24;9(41):7940-7947.
doi: 10.1039/c8sc02303d. eCollection 2018 Nov 7.

Facile saccharide-free mimetics that recapitulate key features of glycosaminoglycan sulfation patterns

Teck Chuan Lim  1 , Shuting Cai  1 , Roland G Huber  2 , Peter J Bond  2   3 , Priscilla Xian Siew Chia  1 , Siv Ly Khou  1 , Shujun Gao  1 , Su Seong Lee  1 , Song-Gil Lee  1
Affiliations

Facile saccharide-free mimetics that recapitulate key features of glycosaminoglycan sulfation patterns

Teck Chuan Lim et al. Chem Sci. .

Abstract

Controlling glycosaminoglycan (GAG) activity to exploit its immense potential in biology ultimately requires facile manipulation of sulfation patterns associated with GAGs. However, satisfying this requirement in full remains challenging, given that synthesis of GAGs is technically arduous while convenient GAG mimetics often produce sulfation patterns that are uncharacteristic of GAGs. To overcome this, we develop saccharide-free polyproline-based GAG mimetics (PGMs) that can be facilely assembled via amide coupling chemistry. Molecular dynamics simulations show that PGMs recapitulate key GAG structural features (i.e. ∼9 Å-sized repeating units, periodicity and helicity) and as with GAGs, can be tuned to introduce systematic variations in sulfate clustering and spacing. Functionally, a variety of PGMs control various GAG activities (concerning P-selectin, neurotrophic factors and heparinase) and exhibit GAG-like characteristics such as progressive modulation, comparable effectiveness with heparins, need for different sequences to suit different activities and the presence of a "minimal bioactive length". Furthermore, PGMs produce consistent effects in vivo and successfully provide therapeutic benefits over cancer metastasis. Taken together with their high level of biosafety, PGMs answer the long-standing need for an effective and practicable strategy to manipulate GAG-appropriate sulfation patterns and exploit GAG activity in medicine and biotechnology.

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Figures

Fig. 1
Fig. 1. Schematic to illustrate similarities in the molecular architecture of natural GAGs and polyprolines (heparin from PDB: 1HPN, chondroitin sulfate from PDB: ; 4N8W, polyproline from CCDC: 1014542).
Fig. 2
Fig. 2. (A) Chemical structures and 3D depictions of PGMs. (B) CD spectra of PGMs. (C) MD simulation results showing the sulfation patterns for heparin, CS-E, {Z}12, {PZ}12, {PZZ}6 and {PPZ}12. Top and bottom structures show respectively the axial cross-sectional view and overall view of superimposed frames over 800 ns. Plot shows the profile of inter-sulfate distances between 1st and selected sulfated proline residues. Sulfate moieties in (A and C) are highlighted in red.
Fig. 3
Fig. 3. Ability of PGMs to modulate GAG activity. Inhibition of CS-E binding to mouse P-selectin by (A) PGMs (n = 4), (C) heparin and tinzaparin (n = 4) and (E) saccharide-based variants of PGMs (n = 4). Inhibition of adhesion of B16-F10 murine melanoma cells to mouse P-selectin by (B) PGMs (n = 9), (D) heparin and tinzaparin (n = 9) and (F) saccharide-based variants of PGMs (n = 9). (G) Inhibition of CS-E binding to human BDNF by PGMs (n = 6). (H) Inhibition of CS-E binding to human NGF-β by PGMs (n = 7). (I) Inhibition of heparinase activity by PGMs (n = 7). Data represent means ± SEM. Statistical analysis was performed by 1- or 2-way ANOVA with post hoc Bonferroni comparison test (*P < 0.05, ***P < 0.001).
Fig. 4
Fig. 4. Translational potential of PGMs. (A) Aggregation of activated mouse platelets in the presence of saline, anti-mouse P-selectin, heparin, tinzaparin and PGMs (n = 9). Data represent means ± SEM. (B) Representative whole mouse bioluminescence images of B16-F10 Red-Fluc metastasis and (C) quantification of tumor burden upon treatment with heparin, tinzaparin and PGMs (n = 13). Box plot shows median with min to max. Statistical analysis was performed by 1-way ANOVA with post hoc Bonferroni comparison test in (A) and by Kruskal–Wallis analysis with Dunn's comparison test in (C) (*P < 0.05, **P < 0.01, ***P < 0.001).
Fig. 5
Fig. 5. (A) Factor IIa activity (n = 4) and (B) clotting time of whole mouse blood (n = 5 for heparins, n = 6 for all others) to evaluate anticoagulation effects of heparin, tinzaparin and PGMs. (C) Levels of albumin, alanine aminotransferase, alkaline phosphatase, bilirubin and urea nitrogen in blood 7 days after intravenous injection of saline or {Z}12 (n = 4 mice). (D) Representative H&E stain of liver and kidney at 1 week to demonstrate in vivo safety of {Z}12 (n = 4 mice). (E) Levels of pro-inflammatory cytokines in mouse blood serum at 2 h after single dose of LPS, saline and {Z}12 and after the last of 5 doses of saline and {Z}12 spaced over a month (n = 5 mice). Scale bar: 100 μm. Data for (A–C), (E) represent means ± SEM.
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