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REVIEW
Contents Vol 73(4)

Natural Inhibitors of Snake Venom Metalloproteinases

Narumi Aoki-Shioi https://orcid.org/0000-0001-8326-6856 A B D , Cho Yeow Koh C and R. Manjunatha Kini B
+ Author Affiliations
- Author Affiliations

A Department of Chemistry, Faculty of Science, Fukuoka University, 19-1, 8-chome Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.

B Department of Biological Sciences, National University of Singapore, Singapore 117543, Republic of Singapore.

C Department of Medicine, Yong Loo Lin School of Medicine, 14 Medical Drive, MD6, Singapore 117599, Republic of Singapore.

D Corresponding author. Email: anarumi@fukuoka-u.ac.jp




Assistant Professor Narumi Aoki-Shioi works in the Department of Chemistry, Faculty of Science, Fukuoka University in Japan. Her research interest is new functional proteins and peptides from venomous snakes and their uses. Her research focuses on functional analysis of snake venom metalloprotease, discovery of endogenous inhibitors from venomous snakes, and analysis of their inhibitory mechanisms for development into therapeutics for snake envenomation. She has written 15 original research papers, four reviews, and one book chapter.


Dr Cho Yeow Koh is a Research Assistant Professor in the Department of Medicine, University of Singapore. He has strong interest in drug discovery and development research related to cardiovascular and neglected tropical diseases. He explores venomous and haematophagous animals for novel molecules that may be developed into therapeutics, medical technologies or research tools. Dr Koh has written 23 peer-reviewed scientific papers and two book chapters, and has eight patents in his name.


Professor R. Manjunatha Kini of the Department of Biological Sciences, National University of Singapore, is a leading authority on structure-function relationships of proteins from venomous animals, especially snakes. He has many years of experience in protein chemistry, biophysics, protein and peptide design and engineering. He has published more than 255 original research papers, reviews and book chapters. He also has 50 patent applications and started two small biotechnology companies. He is the President of the International Society of Toxinology, Vice President of the International Proteolysis Society, and the Editor-in-Chief of Toxin Reviews.

Australian Journal of Chemistry 73(4) 277-286 https://doi.org/10.1071/CH19414
Submitted: 21 September 2019  Accepted: 8 January 2020   Published: 5 March 2020

Abstract

Snakebites are a hazard in the tropical world. Although antivenom therapy is effective, it is beset with inherent drawbacks. A better understanding of the major components of snake venoms and their neutralisation will help in improving snakebite treatment. Snake venom metalloproteinases (SVMPs) are responsible for severe haemorrhage, the inhibition of coagulation and platelet aggregation, observed in the victims of snakebite envenoming. Inhibitors from various sources including medicinal plants, animal venoms, and sera are sought to block the pharmacological functions of SVMPs. In this review, we describe the interaction of natural inhibitors with SVMPs. To understand their inhibitory mechanisms, we focussed on the complex structures of these inhibitors and SVMPs. There are three distinct classes of inhibitors; namely, chelators, competitive inhibitors, and non-competitive inhibitors. A small number of inhibitors show their anti-hemorrhagic activity in in vivo animal models in treatment mode, but most studies evaluate either in vitro neutralisation of enzymatic activity or in vivo effects in pre-incubation protocols. We propose the distinct strategies and limitations to design either broad-spectrum or highly selective SVMP inhibitors. The goal of designing broad-spectrum inhibitors against SVMPs capable of effective treatment of snakebites without toxicity has been elusive, probably because of the narrow molecular footprint of inhibitors against a large number of SVMPs with distinct molecular surfaces. Our ability to design highly selective inhibitors is limited by the lack of information of interactions between selective inhibitors and SVMPs. Comparisons of structures of hemorrhagic and non-hemorrhagic SVMPs revealed different distributions of electric charge on the surface of SVMPs, which may be exploited to design specific inhibitors. The specific inhibitors may also be useful to identify target molecules of the SVMPs and help to understand their mechanism of action.


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