Red Algal Sulfated Galactan Binds and Protects Neural Cells from HIV-1 gp120 and Tat.

Vitor H Pomin,Jason J Paris,Robert J Linhardt,Fuming Zhang,Fakhri Mahdi,Weihua Jin

doi:10.3390/ph14080714

Abstract

The potential neuroprotective capacity of four different sulfated glycans: Botryocladia occidentalis-derived sulfated galactan (BoSG) (MW > 100 kDa), Lytechinus variegatus-derived sulfated fucan (LvSF) (MW~90 kDa), high-molecular weight dextran sulfate (DxS) (MW 100 kDa), and unfractionated heparin (UFH) (MW~15 kDa), was assessed in response to the HIV-1 proteins, R5-tropic glycoprotein 120 (gp120) and/or trans-activator of transcription (Tat), using primary murine neurons co-cultured with mixed glia. Compared to control-treated cells in which HIV-1 proteins alone or combined were neurotoxic, BoSG was, among the four tested sulfated glycans, the only one capable of showing significant concentration-dependent neuroprotection against Tat and/or gp120, alone or combined. Surface plasmon resonance-based data indicate that BoSG can bind both HIV-1 proteins at nM concentrations with preference for Tat (7.5 × 10−8 M) over gp120 (3.2 × 10−7 M) as compared to UFH, which bound gp120 (8.7 × 10−7 M) over Tat (5.7 × 10−6 M). Overall, these data support the notion that sulfated glycan extracted from the red alga B. occidentalis, BoSG, can exert neuroprotection against HIV-1 Tat and gp120, potentially via direct molecular interactions.

Highlights

Human immunodeficiency virus type 1 (HIV-1) infection is associated with neurological symptomatology, including cognitive deficits, affective disorders, and motor impairment [1]
We examined unfractionated heparin (UFH) [25], 100 kDa-dextran sulfate (DxS(100)) [26], the tetrasaccharide repeating sulfated fucan isolated from the sea urchin Lytechinus variegatus (LvSF) [27], and the disaccharide repeating sulfated galactan isolated from the red alga Botryocladia occidentalis (BoSG) [28]
The current results provide evidence that the marine sugars, Botryocladia occidentalis sulfated galactan (BoSG), can efficiently compete with Heparan sulfate proteoglycans (HSPGs) required for Future in vivo studies to assess efficacy and safety of BoSG must be conducted to advance the status of this marine sulfated glycan as a potential drug candidate in phase I clinical trials

Summary

Introduction

Human immunodeficiency virus type 1 (HIV-1) infection is associated with neurological symptomatology, including cognitive deficits, affective disorders, and motor impairment [1]. Neurological symptoms, collectively termed ‘neuroHIV’, persist despite treatment with combined antiretroviral therapeutics (cART), likely due to poor accumulation of cART within the central nervous system where viral neurotoxins promote inflammation and neuronal damage [2,3]. The most well-characterized neurotoxic HIV-1 proteins include the HIV-1 envelope protein, glycoprotein 120 (gp120), and the HIV-1 regulatory protein, trans-activator of transcription (Tat). Through shared and separate neuroinflammatory and excitotoxic mechanisms, gp120 and Tat promote synaptodendritic damage and neuronal death [4,5,6]. The identification of centrally active and safe therapeutics that can ameliorate gp120/Tat-mediated neurotoxicity is important for the improvement of current cART strategies

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