Serine Proteases of Parasitic Helminths

Yang, Yong; Wen, Yun jun; Cai, Ya Nan; Vallée, Isabelle; Boireau, Pascal; Liu, Ming Yuan; Cheng, Siyuan

doi:10.3347/kjp.2015.53.1.1

Cited by 105 publications

(84 citation statements)

References 45 publications

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“…The whole life cycle of the parasite is completed in a single host via the invasion of intestinal epithelial and skeletal muscle cells (Yang et al 2015). Many studies stated that anti-Trichinella drug effects are insufficient.…”

Section: Discussionmentioning

confidence: 99%

Carbonic anhydrase enzyme as a potential therapeutic target for experimental trichinellosis

et al. 2016

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Trichinellosis is a globally distributed helminthic infection. There is a considerable interest in developing new anti-helminthic drugs affecting all the developmental stages of Trichinella. Acetazolamide (carbonic anhydrase (CA) inhibitor) involves a novel mechanism of action by inhibiting such an essential enzyme for parasite metabolism. This work aimed to study the effect of acetazolamide against different stages of T. spiralis in experimental animals. Mice were divided into three groups: group I: infected and treated with acetazolamide on day 2 post infection (P.I.), group II: infected and treated with acetazolamide on day 12 P.I., and group III: infected non-treated. From each group, small intestine and muscles were removed for histopathological and immunohistochemical studies. Also, total adult and muscle larval count were estimated. We found that acetazolamide was effective in reduction of both adult and muscle larval counts. When given early, the effect was more pronounced on the adults (62.7 %). However, the efficacy of the drug against muscle larvae was increased when given late (63 %). Improvement of the intestinal histopathological changes was observed in all the treated groups. Degeneration of encysted larvae with minimal pathologic changes of infected skeletal muscle was observed in the treated groups. Expression of matrix metalloproteinase-9 showed a statistically significant decrease in the intestinal and muscle tissues in all treated groups as compared to the control group. In conclusion, the present study revealed that acetazolamide, carbonic anhydrase inhibitor, could be a promising drug against both adults and larvae of T. spiralis.

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Section: Discussionmentioning

confidence: 99%

Carbonic anhydrase enzyme as a potential therapeutic target for experimental trichinellosis

et al. 2016

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“…Peptidases are secreted by many types of pathogens including bacteria, fungi and parasites and often serve critical roles related to survival and virulence [6–11]. Direct targeting of peptidases expressed by pathogenic organisms has proven to be a successful therapeutic strategy, notably in the development of Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) protease inhibitors [12,13].…”

Section: Introductionmentioning

confidence: 99%

“…The scope and design of the library allows detection of cleavage events from multiple peptidases simultaneously, and the resulting data are informative for understanding activity on both a global and individual enzyme level. Activity-based profiling stands in contrast to traditional proteomics methods that catalog which peptidases are present but do not provide information on how each enzyme contributes to the overall proteolytic activity [11,27]. Likewise, candidate-based approaches focusing on single proteolytic activities isolated from cultures may not accurately represent how these enzymes function within the secreted peptidase milieu [31,32].…”

Section: Introductionmentioning

confidence: 99%

Integrated Activity and Genetic Profiling of Secreted Peptidases in Cryptococcus neoformans Reveals an Aspartyl Peptidase Required for Low pH Survival and Virulence

et al. 2016

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The opportunistic fungal pathogen Cryptococcus neoformans is a major cause of mortality in immunocompromised individuals, resulting in more than 600,000 deaths per year. Many human fungal pathogens secrete peptidases that influence virulence, but in most cases the substrate specificity and regulation of these enzymes remains poorly understood. The paucity of such information is a roadblock to our understanding of the biological functions of peptidases and whether or not these enzymes are viable therapeutic targets. We report here an unbiased analysis of secreted peptidase activity and specificity in C. neoformans using a mass spectrometry-based substrate profiling strategy and subsequent functional investigations. Our initial studies revealed that global peptidase activity and specificity are dramatically altered by environmental conditions. To uncover the substrate preferences of individual enzymes and interrogate their biological functions, we constructed and profiled a ten-member gene deletion collection of candidate secreted peptidases. Through this deletion approach, we characterized the substrate specificity of three peptidases within the context of the C. neoformans secretome, including an enzyme known to be important for fungal entry into the brain. We selected a previously uncharacterized peptidase, which we term Major aspartyl peptidase 1 (May1), for detailed study due to its substantial contribution to extracellular proteolytic activity. Based on the preference of May1 for proteolysis between hydrophobic amino acids, we screened a focused library of aspartyl peptidase inhibitors and identified four high-affinity antagonists. Finally, we tested may1Δ strains in a mouse model of C. neoformans infection and found that strains lacking this enzyme are significantly attenuated for virulence. Our study reveals the secreted peptidase activity and specificity of an important human fungal pathogen, identifies responsible enzymes through genetic tests of their function, and demonstrates how this information can guide the development of high affinity small molecule inhibitors.

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“…Recently there has been a shift of attention to other serine proteases found in this organism and other helminths for the purpose of drug discovery. To this effect, several reviews and research articles have emerged …”

Section: Druggable Proteases In Infectious Organismsmentioning

confidence: 99%

“…In recent years, studies on proteases of pathogenic organisms have been discretely reviewed as potential targets for antiviral, antimalarial, and anthelminthic therapies . The current review aims to highlight the development of potent protease inhibitors for the treatment of infectious diseases, using a holistic approach.…”

Section: Introductionmentioning

confidence: 99%

Proteases and protease inhibitors in infectious diseases

Agbowuro

Huston

Gamble

et al. 2017

Medicinal Research Reviews

173

103

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There are numerous proteases of pathogenic organisms that are currently targeted for therapeutic intervention along with many that are seen as potential drug targets. This review discusses the chemical and biological makeup of some key druggable proteases expressed by the five major classes of disease causing agents, namely bacteria, viruses, fungi, eukaryotes, and prions. While a few of these enzymes including HIV protease and HCV NS3-4A protease have been targeted to a clinically useful level, a number are yet to yield any clinical outcomes in terms of antimicrobial therapy. A significant aspect of this review discusses the chemical and pharmacological characteristics of inhibitors of the various proteases discussed. A total of 25 inhibitors have been considered potent and safe enough to be trialed in humans and are at different levels of clinical application. We assess the mechanism of action and clinical performance of the protease inhibitors against infectious agents with their developmental strategies and look to the next frontiers in the use of protease inhibitors as anti-infective agents.

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Serine Proteases of Parasitic Helminths

Cited by 105 publications

References 45 publications

Carbonic anhydrase enzyme as a potential therapeutic target for experimental trichinellosis

Carbonic anhydrase enzyme as a potential therapeutic target for experimental trichinellosis

Integrated Activity and Genetic Profiling of Secreted Peptidases in Cryptococcus neoformans Reveals an Aspartyl Peptidase Required for Low pH Survival and Virulence

Proteases and protease inhibitors in infectious diseases

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