**4. Biomedical applications**

Studies on *L. obliqua* toxins with a molecular approach have applications beyond the patho‐ physiology and therapeutic perspectives of envenoming. As procoagulant proteins, Lopap and Losac can be useful as tools for developing clotting assays and diagnostic kits. Exogenous factor X activators, such as recombinant Losac, has also the potential to be used for detection of factor X deficiency and lupus anticoagulant [111]. In the case of Lopap, an exogenous prothrombin activator, two patents were applied to use this compound in diagnostic kits for detection of dysprothrombinemias using the native form purified from the venom as well as the recombinant form produced in bacteria. This prothrombin activator has also the potential to be used in clotting time assays, prothrombin assays, and to monitor patients anticoagulated with hirudin. A recent study suggests that exogenous procoagulant proteins could also be considered for therapeutic use to manage bleeding complications caused by anticoagulation therapy. Treatment with Lopap was able to reduce the bleeding time of rabbits anticoagulated with low molecular weight heparin, through direct prothrombin activation, bypassing factor Xa inhibition [112]. Patent information about those applications can be consulted in Table 3.

Modulation of cell responses triggered by *Lonomia* toxins can have valuable therapeutic and biotechnological applications. Promoting cell survival can be useful to improve cell culture technologies and vaccine productions, and for treatment of degenerative diseases. In addition, the effects of Lopap on extracellular matrix remodeling can be valuable to develop wound healing formulations and to regeneration issues (Table 3). For this approaches, design and synthesis of short peptides derived from Lopap amino acid sequence is an interesting task to minimize toxic and side effects and for production of this molecules for proofs of concepts, pre-clinical and clinical tests (Table 3). Isolating specific domains and sequences can also help to understand the multifunctional properties of the studied proteins and direct structurefunction insights.

medical interest in the world, *Lonomia* sp. caterpillars (family: Saturniidae) is the only genus that causes dramatic damages in human blood coagulation [16, 113]. This feature is reflected in the diversity of toxins produced by the caterpillar and their unusual enzymatic properties.

**Table 3.** International patents associated to Lopap and peptides derived from its amino acid sequence. Information

**Publication date Patent Institutions involved**

Toxins from *Lonomia obliqua* — Recombinant Production and Molecular Approach

Instituto Butantan (Brazil); Fapesp (Brazil) and Biolab Sanus Farmacêutica Ltda

http://dx.doi.org/10.5772/53697

197

Instituto Butantan (Brazil); Fapesp (Brazil) and Biolab Sanus Farmacêutica Ltda

Instituto Butantan (Brazil); Fapesp (Brazil) and Biolab Sanus Farmacêutica Ltda

Instituto Butantan (Brazil); Fapesp (Brazil) and Biolab Sanus Farmacêutica Ltda

(Brazil)

(Brazil)

(Brazil)

(Brazil)

prothrombin activator from the bristle of Lonomia obliqua: to be used in diagnosis kits for detecting plasma prothrombin in

prothrombin activating protease (rLopap) in

prothrombin activating protease (rLopap) as well as its amino acid sequence; the use of this protease as a defibrinogenase agent and the diagnosis kit for dysprothrombinemias

uses thereof: it refers to the use of Lopap as modulators of cell death and degeneration caused by wounds, aging and external agents

refers to the uses of Lopap-derived peptides for regenerating tissues and wound repair

monomeric form; the recombinant

hemorrhagic state patients

WO/2003/070746 08.28.2003 Purification and characterization of a

WO/2006/021062 02.03.2006 Process for obtaining the recombinant

WO/2007/028223 03.15.2007 Lopap-based pharmaceutical compositions and

WO/2009093189 07.30.2009 Peptides, compositions, and uses thereof: it

was obtained from World Intellectual Property Organization (WIPO).

Application of molecular approaches in the study of *L. obliqua* toxins has been a valuable strategy in understanding the biological means of these molecules for the source organism itself and the dynamic pathways in envenoming syndrome. On the other hand, this approach reveals these toxins as interesting tools for therapeutic and biotechnological applications. The best examples are Lopap (a prothromin activator lipocalin) and Losac (the only hemolin with proteolytic activity). If, in one hand, the molecular basis of target recognition and proteolysis of factor X and prothrombin by Losac and Lopap, respectively, needs to be further investigated, on the other hand, efforts need to be focused on understanding the pro-survival activity of

both molecules.

**WIPO patent application**

Unveiling the mechanisms of action and structure-function relationship of these multifunc‐ tional molecules may pointing out these molecules as promising candidates to development of new therapeutic drugs, reagents in diagnostic kits for coagulation dysfunctions, and biotechnological applications.
