Targeting Host Cell Furin Proprotein Convertases as a Therapeutic Strategy against Bacterial Toxins and Viral Pathogens

Shiryaev, Sergey A.; Remacle, Albert G.; Ratnikov, Boris I.; Nelson, Nicholas A.; Savinov, Alexei Y.; Ge, Wei; Bottini, Massimo; Rega, Michele F.; Parent, Amélie; Desjardins, Roxane; Fugère, Martin; Day, Robert; Sabet, Mojgan; Pellecchia, Maurizio; Liddington, Robert; Smith, Jeffrey W.; Mustelin, Tomas; Guiney, Donald G.; Lebl, Michal; Strongin, Alex Y.

doi:10.1074/jbc.m703847200

Cited by 98 publications

(96 citation statements)

References 35 publications

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“…These targets represent human proteins and human pathogens of bacterial and viral origin. Earlier studies have proved the efficiency and the accuracy of the custom-built centrifugal synthesizer, and the synthetic scheme we used and the high quality of the synthesized peptides (22,(35)(36)(37). These synthetic peptides were used in the cleavage reactions to identify the cleavage preferences of furin, PC2, PC4, PC5/6, PC7, and PACE4.…”

Section: Resultsmentioning

confidence: 99%

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Substrate Cleavage Analysis of Furin and Related Proprotein Convertases

Remacle

Shiryaev

et al. 2008

Journal of Biological Chemistry

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127

137

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We present the data and the technology, a combination of which allows us to determine the identity of proprotein convertases (PCs) related to the processing of specific protein targets including viral and bacterial pathogens. Our results, which support and extend the data of other laboratories, are required for the design of effective inhibitors of PCs because, in general, an inhibitor design starts with a specific substrate. Seven proteinases of the human PC family cleave the multibasic motifs R-X-(R/K/X)-R2 and, as a result, transform proproteins, including those from pathogens, into biologically active proteins and peptides. The precise cleavage preferences of PCs have not been known in sufficient detail; hence we were unable to determine the relative importance of the individual PCs in infectious diseases, thus making the design of specific inhibitors exceedingly difficult. To determine the cleavage preferences of PCs in more detail, we evaluated the relative efficiency of furin, PC2, PC4, PC5/6, PC7, and PACE4 in cleaving over 100 decapeptide sequences representing the R-X-(R/K/X)-R2 motifs of human, bacterial, and viral proteins. Our computer analysis of the data and the follow-on cleavage analysis of the selected full-length proteins corroborated our initial results thus allowing us to determine the cleavage preferences of the PCs and to suggest which PCs are promising drug targets in infectious diseases. Our results also suggest that pathogens, including anthrax PA83 and the avian influenza A H5N1 (bird flu) hemagglutinin precursor, evolved to be as sensitive to PC proteolysis as the most sensitive normal human proteins.

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Section: Resultsmentioning

confidence: 99%

“…Anthrax PA83 and Pseudomanas exotoxin A (PEx) were purchased from List Laboratories. The ectodomain of avian influenza A H5N1 hemagglutinin precursor (HA) was expressed in a baculoviral expression system and purified as described earlier (22).…”

Section: Methodsmentioning

confidence: 99%

Substrate Cleavage Analysis of Furin and Related Proprotein Convertases

Remacle

Shiryaev

et al. 2008

Journal of Biological Chemistry

Self Cite

127

137

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“…This process occurs through the activation of their toxins and viral proteins by PCs in order to become fully functional [107][108][109]. Indeed, Inhibition of processing of these viral proteins by PC inhibitors completely abrogated the induced cellular cytopathicity [27,[110][111][112]. Then, the infectious capacity of viruses and bacteria requires the presence of host PCs to process their glycoproteins and toxins that are produced as inactive and unprocessed forms.…”

Section: Functional Roles Of Protein Convertases In Health and Diseasesmentioning

confidence: 99%

Processing of peptide and hormone precursors at the dibasic cleavage sites

Rholam

Fahy

2009

Cell. Mol. Life Sci.

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Many functionally important cellular peptides and proteins, including hormones, neuropeptides, and growth factors, are synthesized as inactive precursor polypeptides, which require post-translational proteolytic processing to become biologically active polypeptides. This is achieved by the action of a relatively small number of proteases that belong to a family of seven subtilisin-like proprotein convertases (PCs) including furin. In view of this, this review focuses on the importance of privileged secondary structures and of given amino acid residues around basic cleavage sites in substrate recognition by these endoproteases. In addition to their participation in normal cell functions, PCs are crucial for the initiation and progress of many important diseases. Hence, these proteases constitute potential drug targets in medicine. Accordingly, this review also discusses the approaches used to shed light on the cleavage preference and the substrate specificity of the PCs, a prerequisite to select which PCs are promising drug targets in each disease.

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“…Self-activated PCs are then capable of activating the downstream proteinases, including MMPs. Because of the overlapping substrate preferences and cell/tissue expression, there is a level of redundancy in the functionality of PCs (17)(18)(19).…”

Section: Msmentioning

confidence: 99%