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  • 1
    Language: English
    In: Molecular Immunology, October 2014, Vol.61(2), pp.191-203
    Description: The complement system is an integral component of both innate and adaptive immunity. However, complement is also a pathogenetic factor in many diseases. The development of agents for therapeutic complement inhibition is the topic of intense investigations by many investigators. We have developed a distinctly different therapeutic approach: complement depletion rather than inhibition. This approach is based on cobra venom factor (CVF), a C3 analog known to be able to safely deplete complement. This manuscript will briefly review the structure and activity of CVF, along with its similarities and differences to C3. Exploiting the knowledge of the structure/function relationship of CVF and C3, we created derivatives of human C3 which display the CVF-like activity of depleting complement, referred to as humanized CVF (hCVF). This review describes the structure and activity of hCVF, including the important property of not cleaving C5. The efficacy of hCVF for therapeutic complement depletion in nine preclinical models diseases with complement pathology is reviewed, including reperfusion injury, age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), and immunogenicity of Factor VIII in hemophilia A. Complement depletion is characterized by the absence of toxicity, even after intra-arterial injection into the pulmonary artery of primates. No immunogenicity has been observed.
    Keywords: Cobra Venom Factor (Cvf) ; Humanized Cobra Venom Factor ; Complement Depletion ; Complement Therapeutics ; Medicine ; Biology ; Chemistry
    ISSN: 0161-5890
    E-ISSN: 1872-9142
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  • 2
    Language: English
    In: Toxicon, 2010, Vol.56(7), pp.1198-1222
    Description: Cobra venom factor (CVF) is the complement-activating protein in cobra venom. This manuscript reviews the structure and function of CVF, how it interacts with the complement system, the structural and functional homology to complement component C3, and the use of CVF as an experimental tool to decomplement laboratory animals to study the functions of complement in host defense and immune response as well as in the pathogenesis of diseases. This manuscript also reviews the recent progress in using the homology between CVF and C3 to study C3 structure and function, and to develop human C3 derivatives with the complement-depleting function of CVF. These human C3 derivatives represent humanized CVF, and are a conceptually different concept for pharmacological intervention of the complement system, therapeutic complement depletion. The use of humanized CVF for therapeutic complement depletion in several pre-clinical models of human diseases is also reviewed.
    Keywords: Complement ; Cobra Venom Factor ; Cvf ; Convertase ; Protein Humanization ; Therapeutic Complement Depletion ; Pharmacy, Therapeutics, & Pharmacology ; Anatomy & Physiology
    ISSN: 0041-0101
    E-ISSN: 1879-3150
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 20 December 1994, Vol.91(26), pp.12775-12779
    Description: Cobra venom factor (CVF) is the complement-activating protein in cobra venom. Like C3b, CVF forms with factor B and factor D in human and mammalian serum the bimolecular C3/C5 convertase. This functional similarity of CVF and C3 correlates with many structural similarities, which led to the suggestion that CVF is evolutionally related to C3. We report here the molecular cloning and derived primary structure of CVF. CVF mRNA is 〉5924 nucleotides in length. It contains a single open reading frame of 4926 nucleotides, coding for a pre-pro-protein of 1642 amino acids. The deduced amino acid sequence reveals ≈70% protein similarity to mammalian and human C3 and exceeds 91% in the case of cobra C3. The single-chain pre-pro-CVF consists of a 22-amino acid signal sequence, a 627-amino acid α-chain, and a 989-amino acid precursor chain for the CVF γ- and β-chains. The processing of pro-CVF involves the removal of 4 arginine residues between the α- and precursor chains as well as of the C3a-like and C3d-like domains from the precursor chain, thereby confirming the predicted chain homologies to C3. Pro-CVF contains five potential N-glycosylation sites, of which only three can be expected to be glycosylated in mature CVF. Like C3, pro-CVF contains 27 cysteine residues and a homologous thioester site in the C3d-like region.
    Keywords: Physical sciences -- Physics -- Microphysics ; Physical sciences -- Chemistry -- Chemical compounds ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Physiology ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biochemistry -- Enzymology ; Physical sciences -- Physics -- Microphysics ; Biological sciences -- Biology -- Genetics ; Behavioral sciences -- Anthropology -- Applied anthropology ; Biological sciences -- Biology -- Genetics
    ISSN: 00278424
    E-ISSN: 10916490
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  • 4
    Language: English
    In: Toxicon, August 2012, Vol.60(2), pp.107-107
    Keywords: Pharmacy, Therapeutics, & Pharmacology ; Anatomy & Physiology
    ISSN: 0041-0101
    E-ISSN: 1879-3150
    Source: ScienceDirect Journals (Elsevier)
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  • 5
    Language: English
    In: Toxicon, July 2016, Vol.117, pp.107-107
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.toxicon.2016.04.017 Byline: Carl-Wilhelm Vogel, David C. Fritzinger Author Affiliation: (1) University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA (2) Department of Pathology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, USA Article Note: (miscellaneous) 4. Drug Discovery and Development
    Keywords: Pharmacy, Therapeutics, & Pharmacology ; Anatomy & Physiology
    ISSN: 0041-0101
    E-ISSN: 1879-3150
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  • 6
    Language: English
    In: The open pain journal, 2016, Vol.9, pp.26-37
    Description: Certain types of pain are major unmet medical needs that affect more than 8 percent of the population. Neuropathic pain can be caused by many pathogenic processes including injury, autoimmune disease, neurological disease, endocrine dysfunction, infection, toxin exposure, and substance abuse and is frequently resistant to available pain therapies. The same can be said of postsurgical pain, which can arise from uncontrolled inflammation around the wound site. The complement system is part of the innate immune system and can both initiate and sustain acute and chronic inflammatory pain. Here we review the complement system and original investigations that identify potential drug targets within this system. Drugs that act to inhibit the complement system could fill major gaps in our current standard of care for neuropathic pain states.
    Keywords: Complement ; Complement Inhibition ; Neuropathic Pain ; Post-Operative Pain
    ISSN: 1876-3863
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  • 7
    Language: English
    In: Thrombosis and haemostasis, March 2015, Vol.113(3), pp.548-52
    Description: The complement system is an intrinsic part of the immune system and has important functions in both innate and adaptive immunity. On the other hand, inadvertent or misdirected complement activation is also involved in the pathogenesis of many diseases, contributing solely or significantly to tissue injury and disease development. Multiple approaches to develop pharmacological agents to inhibit complement are currently being pursued. We have developed a conceptually different approach of not inhibiting but depleting complement, based on the complement-depleting activities of cobra venom factor (CVF), a non-toxic cobra venom component with structural and functional homology to complement component C3. We developed a humanised version of CVF by creating human complement component C3 derivatives with complement-depleting activities of CVF (humanised CVF) as a promising therapeutic agent for diseases with complement pathogenesis. Here we review the beneficial therapeutic effect of humanised CVF in several murine models of vascular diseases such as reperfusion injury.
    Keywords: Cvf ; Cobra Venom Factor ; Complement Depletion ; Humanised Cobra Venom Factor ; Reperfusion Injury ; Complement Activation -- Drug Effects ; Complement C3 -- Pharmacology ; Complement Inactivating Agents -- Pharmacology ; Complement System Proteins -- Metabolism ; Elapid Venoms -- Pharmacology ; Immunologic Factors -- Pharmacology ; Reperfusion Injury -- Drug Therapy ; Ventilator-Induced Lung Injury -- Drug Therapy
    ISSN: 03406245
    E-ISSN: 2567-689X
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  • 8
    Language: English
    In: Toxicon, 15 September 2012, Vol.60(4), pp.632-647
    Description: Cobra Venom Factor (CVF) is the complement-activating protein in cobra venom. CVF is structurally and functionally highly homologous to complement component C3. CVF, like C3b, the activated form of C3, forms a bimolecular complex with Factor B in serum, called C3/C5 convertase, an enzyme which activates complement components C3 and C5. Despite the high degree of homology, the two C3/C5 convertases exhibit significant functional differences. The most important difference is that the convertase formed with CVF (CVF,Bb) is physico-chemically far more stable than the convertase formed with C3b (C3b,Bb). In addition, the CVF,Bb convertase and CVF are completely resistant to inactivation by the complement regulatory proteins Factor H and Factor I. Furthermore, the CVF,Bb enzyme shows efficient C5-cleaving activity in fluid phase. In contrast, the C3b,Bb enzyme is essentially devoid of fluid-phase C5-cleaving activity. By taking advantage of the high degree of sequence identity at both the amino acid (85%) and DNA levels (93%) between CVF and cobra C3, we created hybrid proteins of CVF and cobra C3 where sections, or only a few amino acids, of the CVF sequence were replaced with the homologous amino acid sequence of cobra C3. In a first set of experiments, we created five hybrid proteins, termed H1 through H5, where the cobra C3 substitutions collectively spanned the entire length of the CVF protein. We also created three additional hybrid proteins where only four or five amino acid residues in CVF were exchanged with the corresponding amino acid residues from cobra C3. Collectively, these hybrid proteins, representing loss-of-function mutants of CVF, allowed the identification of regions and individual amino acid residues important for the CVF-specific functions. The results include the observation that the CVF β-chain is crucially important for forming a stable convertase, whereas the CVF α-chain appears to harbor no CVF-specific functions. Furthermore, the CVF γ-chain is additionally important for the fluid-phase C5-cleaving activity of CVF,Bb. Interestingly, the structural changes in the individual hybrid proteins differentially affected the molecular functions of the CVF,Bb enzyme such as convertase formation, C3 cleavage, and C5 cleavage.
    Keywords: Cobra Venom Factor ; Complement ; Complement Component C3 ; C3 Convertase ; Hybrid Proteins ; Cobra (Naja Sp.) ; Pharmacy, Therapeutics, & Pharmacology ; Anatomy & Physiology
    ISSN: 0041-0101
    E-ISSN: 1879-3150
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  • 9
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 01 August 1995, Vol.92(16), pp.7605-7605
    Keywords: Biological sciences -- Biochemistry -- Biomolecules
    ISSN: 00278424
    E-ISSN: 10916490
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  • 10
    Language: English
    In: Molecular Immunology, 2010, Vol.47(13), pp.2268-2268
    Keywords: Medicine ; Biology ; Chemistry
    ISSN: 0161-5890
    E-ISSN: 1872-9142
    Source: ScienceDirect Journals (Elsevier)
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