Heparin-binding Peptides as Novel Therapies to Stop SARS-CoV-2 Cellular Entry and Infection

Abstract

Heparan sulfate proteoglycans (HSPGs) are cell surface receptors that are involved in the cellular uptake of pathologic amyloid proteins and viruses, including the novel coronavirus; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Heparin and heparan sulfate antagonize the binding of these pathogens to HSPGs and stop their cellular internalization, but the anticoagulant effect of these agents has been limiting their use in the treatment of viral infections. Heparin-binding peptides (HBPs) are suitable nonanticoagulant agents that are capable of antagonizing binding of heparin-binding pathogens to HSPGs. Here, we review and discuss the use of HBPs as viral uptake inhibitors and will address their benefits and limitations to treat viral infections. Furthermore, we will discuss a variant of these peptides that is in the clinic and can be considered as a novel therapy in coronavirus disease 2019 (COVID-19) infection. SIGNIFICANCE STATEMENT: The need to discover treatment modalities for COVID-19 is a necessity, and therapeutic interventions such as heparin-binding peptides (HBPs), which are used for other cases, can be beneficial based on their mechanisms of actions. In this paper, we have discussed the application of HBPs as viral uptake inhibitors in COVID-19 and explained possible mechanisms of actions and the therapeutic effects.

Graphical abstract

Fig. 1.

HBPs mode of action. (A) Heparin-binding viruses dock to their cellular receptors (HSPGs) and hijack HSPG-mediated endocytosis to enter cells. (B) Pretreatment of cells with HBPs or viral incubation with HBPs results in neutralizing HSPGs or viruses with HBPs, respectively. This neutralization antagonizes the virus-HSPG binding and leads to a reduction in the level of viral uptake.

Fig. 2.

Cellular trafficking of viruses and HBPs. (A) Upon HSPG-mediated endocytosis, viruses enter the endosomal pathway but escape from endosomes to enter the cytoplasm and reach to the nucleus to start replication or exit from cells to transfect neighboring cells. (B) HBPs also internalize by HSPG-mediated endocytosis and enter the endosomal-lysosomal system, but they are not capable of escaping endosomes. Thus, HBPs will be sorted to the lysosome for degradation and cannot reach cytoplasmic viruses. (C) Conjugates of HBP-CRM-197 use CRM-197 receptor to enter the endosomal pathway, but CRM-197 can escape endosomes before reaching to lysosomes for degradation.

Fig. 3.

HBPs docking to SARS-CoV-2 spike protein S1. (A) Docking model showing the interaction of heparin-binding domains of spike protein S1 (yellow) and CRM-197 (rainbow). (B) Docking model showing the interaction of P5 + 14 peptide (rainbow) with the heparin-binding domain of spike protein S1 (yellow). (C) Docking model showing the interaction of control peptide (rainbow) with the heparin-binding domain of spike protein S1 (yellow). (D) Detailed docking model of results in (A) showing molecular interactions between spike protein S1 (yellow) and CRM-197 (blue). Electrostatic interactions between residues are shown as white dotted lines. Protein spike S1 residues involved in the interaction are shown. Binding involves interaction between Asn-354, Arg-357, Lys-356, Leu-335, Leu-335, Cys-336, Asn-343, Asn-343, Arg-346, Arg-346, Asn-450, Arg-346, Glu-340, Thr-345, Thr-345, and Thr-345 residues from spike protein S1 and Glu-249, Gln-252, Glu-248, Thr-256, Lys-264, Gly-268, Pro-271, Asn-270, Glu-241, Glu-240, Glu-241, Glu-248, His-251, Ala-276, Ala-276, and Asn-277 residues from CRM-197. (E) Detailed docking model of results in (B) showing molecular interactions between spike protein S1 (yellow) and N-terminus of P5 + 14 (red). Electrostatic interactions between residues are shown as white dotted lines. Protein spike S1 residues involved in the interaction are shown. Binding involves interaction between Asp-428, Asp-571, and Asp-571 residues from spike protein S1 and Lys-20, Ala-10, and Lys-6 residues from P5 + 14 peptide. (F) Detailed docking model of results in (B) showing molecular interaction between spike protein S1 (yellow) and C-terminus of P5 + 14 (blue). Electrostatic interactions between residues are shown as white dotted lines. Protein spike S1 residues involved in the interaction are shown. Binding involves interaction between Thr-470, Thr-470, Ser-469, Ser-469, Ser-469, Glu-471, Asp-467, Asn-460, Arg-466, Glu-465, and Glu-465 residues from spike protein S1 and Gln-42, Ala-35, Lys-37, Ala-38, Lys-34, Ala-38, Ala-35, Lys-34, Gln-31, Gln-31 and Gln-28 from P5 + 14 peptide.