Natural Inhibitors of Snake Venom Metalloproteinases

2020 ◽  
Vol 73 (4) ◽  
pp. 277
Author(s):  
Narumi Aoki-Shioi ◽  
Cho Yeow Koh ◽  
R. Manjunatha Kini

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 invivo animal models in treatment mode, but most studies evaluate either invitro neutralisation of enzymatic activity or invivo 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.

Author(s):  
Ana G. C. Neves-Ferreira ◽  
Richard H. Valente ◽  
Gilberto B. Domont ◽  
Jonas Perales

2015 ◽  
pp. 1-23
Author(s):  
Ana G. C. Neves-Ferreira ◽  
Richard H. Valente ◽  
Gilberto B. Domont ◽  
Jonas Perales

2020 ◽  
Vol 56 (68) ◽  
pp. 9787-9790
Author(s):  
Yuko P. Y. Lam ◽  
Cookson K. C. Chiu ◽  
Christopher A. Wootton ◽  
Ian Hands-Portman ◽  
Meng Li ◽  
...  

A diagram to show the differences between wild-type and deamidated hIAPPs interaction with site specific and non-specific inhibitors.


1960 ◽  
Vol 13 (1-2) ◽  
pp. 43-51 ◽  
Author(s):  
HISASHI KONDO ◽  
SATORU KONDO ◽  
HIROO IKEZAWA ◽  
RYOSUKE MURATA ◽  
AKIRA OHSAKA

Toxicon ◽  
2005 ◽  
Vol 45 (8) ◽  
pp. 1013-1020 ◽  
Author(s):  
Jonas Perales ◽  
Ana G.C. Neves-Ferreira ◽  
Richard H. Valente ◽  
Gilberto B. Domont

Toxins ◽  
2016 ◽  
Vol 8 (9) ◽  
pp. 250 ◽  
Author(s):  
Viviane Bastos ◽  
Francisco Gomes-Neto ◽  
Jonas Perales ◽  
Ana Neves-Ferreira ◽  
Richard Valente

2018 ◽  
Author(s):  
André da Silva Santiago ◽  
Rafael M. Couñago ◽  
Priscila Zonzini Ramos ◽  
Paulo H. C. Godoi ◽  
Katlin B. Massirer ◽  
...  

The calcium/calmodulin-dependent protein kinases (CAMKKs) are upstream activators of CAMK1 and CAMK4 signalling and have important functions in neural development, maintenance and signalling, as well as in other aspects of biology such as Ca2+ signalling in the cardiovascular system. To support the development of specific inhibitors of CAMKKs we have determined the crystal structure of CAMKK1 with two ATP-competitive inhibitors. The structures reveal small but exploitable differences between CAMKK1 and CAMKK2, despite the high sequence identity, which could be used in the generation of specific inhibitors. Screening of a kinase inhibitor library revealed molecules that bind potently to CAMKK1. Isothermal titration calorimetry revealed that the most potent inhibitors had binding energies largely dependent on favourable enthalpy. Together, the data provide a foundation for future inhibitor development activities.


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