Title: Elucidating the structural requirements for heparin-based inhibitors of SARS-CoV-2 infection
Funder: The Academy of Medical Sciences

Abstract: Heparin, the second most widely-used drug by weight globally, is formulated as a polydisperse, heterogenous biopharmaceutical. Unfractionated heparin and low molecular weight heparins are clinically approved as anticoagulants/thrombotics with excellent safety, stability, bioavailability, and pharmacokinetic profiles. Heparin possesses broad-spectrum activity against a multitude of distinct viruses, including previous SARS-associated coronavirus and current SARS-CoV-2, alongside beneficial anti-inflammatory properties. Furthermore, research within my laboratory and collaborators has demonstrated that heparin and its cell surface analogue heparan sulfate interact with the SARS-CoV-2 Spike RBD and that heparan sulfate is an essential co-receptor for SARS-CoV-2 infection. This research showed the structure:function requirements for these interactions, which has been used to underpin numerous, current clinical trials involving heparin. Crucially, heparin has proven key therapeutic properties that are of relevance to the treatment and survival of COVID-19 patients. However, genomic studies show that SARS-CoV-2 is evolving where Variants of Concern are abundant and some of these bear mutations in the spike protein; these changes are now associated with increased infectivity, disease severity, and immune evasion. Additionally, evidence of recombination between circulating strains indicates positive selection for such Spike variants. A representative array of Variants of Concern has been identified and using recombinant protein expression, will be produced and characterised in terms of heparin-binding interactions, to extract the structural insights that underpin the mechanism of infection; these can be further exploited for the development of tailor-made, heparin-based drugs to meet both the ongoing and future antiviral challenges.

Lay abstract: Drug development processes are slow and ineffective against emerging health threats. Repurposing existing drugs that can treat SARS-CoV-2 infections provides a timely and attractive alternative. Currently, there are limited commercially available medicinal products designed to treat COVID-19, and there is increasing concern regarding the emergence of highly contagious Variants of Concern and their resistance towards the immunity gained by both natural infection and vaccination. Heparin, a well-tolerated anticoagulant drug, has been used safely in medicine for >80 years. Alongside its anticoagulant activities, it can also stop viruses from causing us disease, including the current coronavirus responsible for the COVID-19 pandemic. SARS-CoV-2 is the seventh member of the beta-coronavirus and now there is compelling evidence that shows it is going through genetic change, creating Variants of Concern that are responsible to increased disease severity. Some of these genetic changes occur in the Spike protein, which is how the virus gains entry into human cells and where heparin plays a role. Understanding how and why these mutated strains alter and increase the pathogenicity of SARS-CoV-2 is crucial. Ultimately, a complete appreciation of these mechanisms will underpin the strategy of drug development to prepare for the next stage of the ongoing and future outbreaks, as current heparin-based interventions are likely to need adaption to counter future mutation(s): exploring distinct properties within the structure of heparin that facilitates the binding to, and subsequent entry of, human cells will deliver proof-of-concept for next-generation, tailored heparin-based antiviral drugs to tackle future viral outbreaks.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION