A PROTEIN FROM NOSE-HORNED VIPER VENOM HOLDS PROMISE FOR THE DEVELOPMENT OF AN INNOVATIVE DRUG FOR VENOUS THROMBOEMBOLISM

Abstract

Investigating modes of action of natural toxins and venoms frequently inspire new therapies. Namely, many toxins precisely target specific receptors or pathways in organisms. For example, glucagon-like peptide-1-based drugs to treat diabetes and obesity, like Ozempic, were developed based on a peptide toxin from the venom of lizard Gila monster. In the venom of the nose-horned viper, we discovered and characterized the protein VaaSPH-1, which strongly inhibits blood coagulation via the intrinsic pathway. All current therapies for the prevention of venous thrombosis carry a high risk of severe bleeding as a side effect. Although numerous efforts have been made to improve treatment, no major breakthroughs have yet been achieved. The structure and mode of action of VaaSPH-1 are unique, making it a promising basis for the development of a safer anticoagulant drug for the treatment of venous thromboembolism that includes deep vein thrombosis and pulmonary embolism. Here, we describe our strategy for the development of innovative low molecular mass anticoagulant based on the structure of VaaSPH-1. The most promising candidate molecules are already in the process of patent protection.

Protein iz strupa modrasa obeta razvoj inovativnega zdravila za zdravljenje venske trombembolije

Izvleček: Preučevanje načinov delovanja naravnih toksinov in strupov pogosto navdahne razvoj novih načinov zdravljenja. Številni toksini namreč zelo natančno prizadenejo specifične receptorje ali signalne poti v organizmih. Na primer učinkovine homologne glukagonu podobnemu peptidu-1 za zdravljenje sladkorne bolezni in debelosti, kot je Ozempic, so bile razvite na osnovi peptidnega toksina iz strupa kuščarja gilske pošasti (Gila monster). V strupu modrasa smo odkrili in opisali protein VaaSPH-1, ki močno zavira strjevanje krvi po intrinzični poti. Vse trenutno dostopne terapije za preprečevanje venske tromboze so tvegane za pojav hudih krvavitev kot stranskega učinka. Kljub številnim prizadevanjem za izboljšanje zdravljenja te patologije večjega preboja še ni bilo. Struktura in način delovanja VaaSPH-1 sta edinstveni, zato ta molekula predstavlja obetavno osnovo za razvoj varnejše antikoagulantne učinkovine za zdravljenje venske trombembolije, ki vključuje trombozo globokih ven in pljučno embolijo. V članku je opisana strategija razvoja inovativnega nizkomolekularnega antikoagulanta na osnovi strukture VaaSPH-1. Najobetavnejše kandidatne molekule so že v postopku pridobivanja patentne zaščite.

Ključne besede: kačji strup; hemostaza; inhibitor intrinzične tenaze; antagonist FIXa; antikoagulant; venska tromboza