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Heparin Crisis: Problems Solved and Solutions Found

Close up of a giant African snail sat of a rock.
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A research team from Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, has discovered an alternative, novel source of the important anticoagulant heparin. Acharan sulfate, a heparin-like substances (HLS), was extracted from the mucus of the giant African snail, Achatina fulica, organically farmed by households around Khaoyai National Park in Thailand. The work has been published in Carbohydrate Research.


A possible heparin shortage

The supply chain in the pharmaceutical industry has always been a prime target for counterfeiters and suppliers delivering substandard and adulterated products. One of the most serious incidents in the past decade was the contamination of raw heparin stock with infectious virus derived from pigs’ intestines. This caused many deaths and led to a major recall of the injectable anticoagulant by the US Food and Drug Administration (FDA) and their equivalents in Europe, Australia and New Zealand.


There are great concerns around the use of porcine raw materials for drug development and manufacturing, due mainly to animal infectious disease epidemics, including swine flu (H1N1) and African swine fever (ASF).


Anticoagulant therapy, mainly with low molecular weight heparin (LMWH), boosts the survival rate of COVID-19-infected patients with coagulopathy. The increasing incidence of cardiovascular and other chronic disorders has also led to robust adoption of heparin in various applications, leading to a shortage of raw materials and increased costs associated with LMWH. Consequently, there is a strong need for a highly rich alternative source of heparin.


Outline of a human body showing the internal organs. Arrows coming off indicate areas where heparin can be used in clinical treatments.

Figure 1: An outline of some of heparin’s therapeutic applications. Credit: Aden International Co. Ltd.


A novel heparin supply from an unlikely source

Mucus was harvested from giant African snails, precipitated and digested with enzymes. Strong anion exchange chromatography was then used to divide the product to isolate the active fraction. High-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) spectroscopy were used to perform structural characterization of the potential heparin equivalent. The ability of the active fraction to inhibit binding of the SARS-CoV-2 spike protein to the ACE-2 receptor was then tested using a binding assay kit.


A flow diagram showing the experimental steps used in the isolation and purification of HLS from giant African snail mucus.

Figure 2: Illustration of the experimental workflow. Mucus from the giant African snail (Achatina fulica) was harvested, precipitated and digested with enzymes. It was then isolated into three fractions, using strong anion exchange chromatography to obtain HLS-F3. Credit: Aden International Co. Ltd.


The key findings of the paper were:

  • The research team discovered an HLS, called acharan sulfate (AS), which is a unique sulfated glycosaminoglycans (GAGs) equivalent to heparin found in mast cells, in rich “extracted” Achatina mucus.
  • The snail-derived HLS is structurally equivalent to heparin and therefore likely to have strong anticoagulant activity and potential therapeutic uses.
  • In vitro laboratory experiments showed that it was also able to inhibit binding of SARS CoV-2 spike protein to the host ACE2.
  • Snail HLS is free from health-hazardous contamination due to their short production processes.
  • The yield of the active purified HLS is acceptably high.

 

A sustainable solution to an important problem

Heparin/LMWH extracted from GAG in snail mucus is a novel alternative source of this important drug that offers improved safety over porcine- and bovine-based products. The availability, accessibility and acceptability of snail mucus/heparin guarantee the overall sustainability of supply in response to the increasing demand over time by organic farm management. FDAs worldwide can benefit from the above discovery.


It should be noted that these results are currently based on laboratory experiments. In vitro and in vivo experiments have yet to prove the anticoagulant properties of the novel HLS. The investigation of the ability of the HLS to block SARS-CoV-2 binding is not conclusive evidence of its ability to treat COVID-19.


A bright future for snail mucus?

Patents have subsequently been filed for the snail mucus collection process and its uses (Patent no. WO2021/080519A1) and the novel method of extraction, purification and characterization of HLS from the giant African snail (Patent no. WO2022/1500181A1), with the hope of making this proof-of-concept a realistic clinical option for medicine. Further work is required to validate inferences made from the structural data about the anticoagulant and therapeutic potential of the HLS.


Further work is also needed to assess the logistics and viability of the process for real-world, large-scale manufacturing.


References


1. Kodchakorn K, Chokepaichitkool T, Kongtawelert P. Purification and characterisation of heparin-like sulfated polysaccharides with potent anti-SARS-CoV-2 activity from snail mucus of Achatina fulica. Carbohydr Res. 2023;529:108832. doi:10.1016/j.carres.2023.108832


2. WIPO Patent # WO2021/080519A1, Snail Mucus Collection Process

and Its Use , 2021.


3. WIPO Patent # WO2022/150018A1, A Novel Method of Isolation,

Purification and Characterization of Heparin-Like Substances from snail mucus (Achatina fulica) and Its Use, 2022. 


Aden International Co., Ltd. developed an organic snail farm in compliance with COSMOS (COSMetic Organic and Natural Standard) under the supervision of the International Federation of Organic Agriculture Movements (IFOAM), snail products, acquiring the patent under the World Intellectual Property Organization/ Patent Cooperation Treaty (WIPO/PCT), Patent no. WO2021/080519A1 (snail mucus collection process and its uses). The novel method of extraction, purification and characterization of HLS from the giant African snail (Achatina fulica) and their uses (Patent no. WO2022/1500181A1) have been invented by the research team mentioned above and is owned by Aden International Co., Ltd. The latter patent has to be used in parallel with the former one.


About the authors:

Prof. Prachya Kongtawelert PhD, Department of Biochemistry, Chiang Mai University.

Kitpong Puttarathuvanun, founder & CEO Aden International Co., Ltd.

Pich Nitsmer PhD, Chiang Mai University.