Bacterial resistance to conventional antibiotics is a global threat that has spurred the development of antimicrobial peptides (AMPs) and their mimetics as novel anti-infective agents. While the ...bioavailability of AMPs is often reduced due to protease activity, the non-natural structure of AMP mimetics renders them robust to proteolytic degradation, thus offering a distinct advantage for their clinical application. We explore the therapeutic potential of N-substituted glycines, or peptoids, as AMP mimics using a multi-faceted approach that includes in silico, in vitro, and in vivo techniques. We report a new QSAR model that we developed based on 27 diverse peptoid sequences, which accurately correlates antimicrobial peptoid structure with antimicrobial activity. We have identified a number of peptoids that have potent, broad-spectrum in vitro activity against multi-drug resistant bacterial strains. Lastly, using a murine model of invasive S. aureus infection, we demonstrate that one of the best candidate peptoids at 4 mg/kg significantly reduces with a two-log order the bacterial counts compared with saline-treated controls. Taken together, our results demonstrate the promising therapeutic potential of peptoids as antimicrobial agents.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Increased multiple antibiotic resistance in the face of declining antibiotic discovery is one of society’s most pressing health issues. Antimicrobial peptides represent a promising new class of ...antibiotics. Here we ask whether it is possible to make small broad spectrum peptides employing minimal assumptions, by capitalizing on accumulating chemical biology information. Using peptide array technology, two large random 9-amino-acid peptide libraries were iteratively created using the amino acid composition of the most active peptides. The resultant data was used together with Artificial Neural Networks, a powerful machine learning technique, to create quantitative in silico models of antibiotic activity. On the basis of random testing, these models proved remarkably effective in predicting the activity of 100,000 virtual peptides. The best peptides, representing the top quartile of predicted activities, were effective against a broad array of multidrug-resistant “Superbugs” with activities that were equal to or better than four highly used conventional antibiotics, more effective than the most advanced clinical candidate antimicrobial peptide, and protective against Staphylococcus aureus infections in animal models.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Tuberculosis is an ongoing threat to global health, especially with the emergence of multi drug-resistant (MDR) and extremely drug-resistant strains that are motivating the search for new treatment ...strategies. One potential strategy is immunotherapy using Innate Defence Regulator (IDR) peptides that selectively modulate innate immunity, enhancing chemokine induction and cell recruitment while suppressing potentially harmful inflammatory responses. IDR peptides possess only modest antimicrobial activity but have profound immunomodulatory functions that appear to be influential in resolving animal model infections. The IDR peptides HH2, 1018 and 1002 were tested for their activity against two M. tuberculosis strains, one drug-sensitive and the other MDR in both in vitro and in vivo models. All peptides showed no cytotoxic activity and only modest direct antimicrobial activity versus M. tuberculosis (MIC of 15-30 µg/ml). Nevertheless peptides HH2 and 1018 reduced bacillary loads in animal models with both the virulent drug susceptible H37Rv strain and an MDR isolate and, especially 1018 led to a considerable reduction in lung inflammation as revealed by decreased pneumonia. These results indicate that IDR peptides have potential as a novel immunotherapy against TB.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
The rise of antibiotic resistance has lead to the search for new therapeutics against bacterial infections. Innate defence regulators (IDRs), synthetic versions of natural host defence ...peptides, are being developed as anti-infective agents due to their immunomodulatory properties. HDPs have been shown to suppress infections by boosting leukocyte recruitment, while limiting harmful inflammation. To optimize the IDR regulatory function, we developed peptide 1002, a bactenecin derivative, by screening a peptide library for enhanced leukocyte chemoattractants induction in human blood mononuclear cells (hBMC). 1002 enhanced protection in a Staphylococcus aureus murine infection model, correlating with increased chemokine production and leukocyte recruitment. 1002 also suppressed inflammatory cytokine production by lipopolysaccharide-stimulated hBMC. IDRs are being deciphered to assist in their development as therapeutics. We found that 1002 regulation is dependent on the PI3-Kinase pathway, a signal cascade that regulates immune and inflammatory responses. PI3-K inhibition abrogated 1002-mediated chemokine induction and reduced its anti-inflammatory properties. 1002 influence on PI3-K signalling was confirmed by examining responses of pathway elements and by systems biology microarray analysis of the immune network by InnateDB. Understanding the mechanisms of IDR immune regulation via PI3-K modulation will aid in their development as novel anti-infective agents. This work was supported by Genome BC and Genome Prairie for the Pathogenomics of Innate Immunity Research Program, and by FNIH and CIHR through the Grand Challenges in Global Health Initiative.
Bacterial resistance to conventional antibiotics is a global threat that has spurred the development of antimicrobial peptides (AMPs) and their mimetics as novel anti-infective agents. While the ...bioavailability of AMPs is often reduced due to protease activity, the non-natural structure of AMP mimetics renders them robust to proteolytic degradation, thus offering a distinct advantage for their clinical application. We explore the therapeutic potential of N-substituted glycines, or peptoids, as AMP mimics using a multi-faceted approach that includes in silico, in vitro, and in vivo techniques. We report a new QSAR model that we developed based on 27 diverse peptoid sequences, which accurately correlates antimicrobial peptoid structure with antimicrobial activity. We have identified a number of peptoids that have potent, broad-spectrum in vitro activity against multi-drug resistant bacterial strains. Lastly, using a murine model of invasive S. aureus infection, we demonstrate that one of the best candidate peptoids at 4 mg/kg significantly reduces with a two-log order the bacterial counts compared with saline-treated controls. Taken together, our results demonstrate the promising therapeutic potential of peptoids as antimicrobial agents.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IDRs as Novel Immunomodulators (B208) Guarna, Marta; Yang, Haiyan; Glavas, Natalie ...
The Journal of immunology (1950),
04/2007, Volume:
178, Issue:
1_Supplement
Journal Article
Peer reviewed
Abstract
Inimex Innate Defence Regulators (IDRs) are novel, synthetic immunomodulatory peptides that protect against infections by selectively activating the innate immune system while regulating ...inflammation. The multi-faceted effects of IDRs are mediated primarily by monocytes and macrophages. These cells respond to IDRs by selectively increasing the expression of cell surface receptors, and cytokines and chemokines (MCP-1, MCP-3 and CCL-5) which trigger the recruitment and activation of immune cells to the site of the infection. In addition, IDRs control inflammation by enhancing the expression of the anti-inflammatory cytokine IL-10, and down-regulating the release of pro-inflammatory cytokines TNF-α and IL-6 in response to pathogen-associated stimuli. As a result, IDRs selectively activate the immune system without concomitant up-regulation of inflammatory responses. This combination of IDR effects is a distinctive quality of these agents since they are able to maintain a balance between immunostimulatory and inflammatory responses to an invading pathogen.
Haiyan Yang is the recipient of an NSERC Industrial R&D Fellowship.
Funded in part by a grant from the FNIH and the CIHR through the Grand Challenges in Global Health initiative
Tuberculosis is an ongoing threat to global health, especially with the emergence of multi drug-resistant (MDR) and extremely drug-resistant strains that are motivating the search for new treatment ...strategies. One potential strategy is immunotherapy using Innate Defence Regulator (IDR) peptides that selectively modulate innate immunity, enhancing chemokine induction and cell recruitment while suppressing potentially harmful inflammatory responses. IDR peptides possess only modest antimicrobial activity but have profound immunomodulatory functions that appear to be influential in resolving animal model infections. The IDR peptides HH2, 1018 and 1002 were tested for their activity against two M. tuberculosis strains, one drug-sensitive and the other MDR in both in vitro and in vivo models. All peptides showed no cytotoxic activity and only modest direct antimicrobial activity versus M. tuberculosis (MIC of 15-30 mu g/ml). Nevertheless peptides HH2 and 1018 reduced bacillary loads in animal models with both the virulent drug susceptible H37Rv strain and an MDR isolate and, especially 1018 led to a considerable reduction in lung inflammation as revealed by decreased pneumonia. These results indicate that IDR peptides have potential as a novel immunotherapy against TB.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nonselective antagonists of voltage-gated sodium (NaV) channels have been long used for the treatment of epilepsies. The efficacy of these drugs is thought to be due to the block of sodium channels ...on excitatory neurons, primarily NaV1.6 and NaV1.2. However, these currently marketed drugs require high drug exposure and suffer from narrow therapeutic indices. Selective inhibition of NaV1.6, while sparing NaV1.1, is anticipated to provide a more effective and better tolerated treatment for epilepsies. In addition, block of NaV1.2 may complement the anticonvulsant activity of NaV1.6 inhibition. We discovered a novel series of aryl sulfonamides as CNS-penetrant, isoform-selective NaV1.6 inhibitors, which also displayed potent block of NaV1.2. Optimization focused on increasing selectivity over NaV1.1, improving metabolic stability, reducing active efflux, and addressing a pregnane X-receptor liability. We obtained compounds 30–32, which produced potent anticonvulsant activity in mouse seizure models, including a direct current maximal electroshock seizure assay.
Nonselective antagonists of voltage-gated sodium (Na
) channels have been long used for the treatment of epilepsies. The efficacy of these drugs is thought to be due to the block of sodium channels ...on excitatory neurons, primarily Na
1.6 and Na
1.2. However, these currently marketed drugs require high drug exposure and suffer from narrow therapeutic indices. Selective inhibition of Na
1.6, while sparing Na
1.1, is anticipated to provide a more effective and better tolerated treatment for epilepsies. In addition, block of Na
1.2 may complement the anticonvulsant activity of Na
1.6 inhibition. We discovered a novel series of aryl sulfonamides as CNS-penetrant, isoform-selective Na
1.6 inhibitors, which also displayed potent block of Na
1.2. Optimization focused on increasing selectivity over Na
1.1, improving metabolic stability, reducing active efflux, and addressing a pregnane X-receptor liability. We obtained compounds
, which produced potent anticonvulsant activity in mouse seizure models, including a direct current maximal electroshock seizure assay.
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