Abstract
The hirudin-like factors 3 (HLF3) and 4 (HLF4) belong to a new class of leech-derived factors and are present in specimens of the three European medicinal leeches, Hirudo medicinalis, Hirudo verbana, and Hirudo orientalis, respectively. Here we describe the functional analysis of natural and synthetic variants of HLF3 and HLF4. Whereas the natural variants display only very low or no detectable anti-coagulatory activities, modifications within the N-termini in combination with an exchange of the central globular domain have the potency to greatly enhance the inhibitory effects of respective HLF3 and HLF4 variants on blood coagulation. Our results support previous observations on the crucial importance of all parts (both the N- and C-termini as well as the central globular domains) of hirudin and HLF molecules for thrombin inhibition.
Highlights
The saliva of hematophagous leeches comprises a complex mixture of bioactive molecules (Ascenzi et al 1995; Baskova and Zavalova 2001; Baskova et al 2008; Hildebrandt and Lemke 2011)
hirudin-like factors (HLFs) comprise structural features that are characteristic for hirudins but may considerably differ in biochemical properties like molecular weight (MW) and isoelectric point
We have described the purification and functional characterization of HLF1 (Müller et al 2016) and HLF5, 6, and 8 (Lukas et al 2019), respectively
Summary
The saliva of hematophagous leeches comprises a complex mixture of bioactive molecules (Ascenzi et al 1995; Baskova and Zavalova 2001; Baskova et al 2008; Hildebrandt and Lemke 2011). The hirudin-like factors (HLFs) represent a recently described subclass of compounds derived from the salivary glands of medicinal leeches of the genera Hirudo and Hirudinaria (Müller et al 2016; Müller et al 2017). HLFs comprise structural features that are characteristic for hirudins (e.g., six cysteine residues within a central globular domain and a common gene structure composed of four exons and three introns) but may considerably differ in biochemical properties like molecular weight (MW) and isoelectric point. We have described the purification and functional characterization of HLF1 (originating from Hirudo medicinalis) (Müller et al 2016) and HLF5, 6, and 8 (originating from Hirudinaria manillensis) (Lukas et al 2019), respectively. While HLF1 and HLF6 did not exhibit any measurable anti-coagulatory activities, both HLF5 and HLF8 did
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