Wednesday, February 26, 2020 8:15:59 AM
in "defensin" of IPIX
lol, TIAB, but not so much - getting BRI in front of virologists, BARDA, is absolutely the right thing to do and time well spent, not just in inc Viz to company/BRI-platform, but who knows if Uncle Sam, others, wake up to potential. academics and rookie research geeks like me have long BRI-(HDP-M)believed. maybe it's our time in the sickening face of Cvirus. lots of lit out there on Defensins/AMP (esp synthesized, optimized ones that overcome the dev challenges of natural Defensins/AMPs). just go to google scholar. a few lifts below i did while sipping coffee. if BRI, leading Swiss Army Knife in Clinical Dev, shows even miniminal anti-viral activity, via the MTAs, and more imptly against COVID-19, well, let's see how busy Leo's phone becomes, inbound. could easily see NIH backing to do a single-dose IV trial to see if helps w sickest patients, with BRI vaccine a longer a play. let's get those MTAs executed and see what BRI might be able to do.
some scientific-based BRI-believing (BRI-Be-Liv-ing) reading before your shift in the ED, good doctor
----
Defensins in innate immunity
https://journals.lww.com/co-hematology/Abstract/2014/01000/Defensins_in_innate_immunity.8.aspx
Summary
Defensins are the ‘Swiss army knife’ in innate immunity against microbial pathogens. Their modes of action are often reminiscent of the story of ‘The Blind Men and the Elephant’. The functional diversity and mechanistic complexity, as well as therapeutic potential of defensins, will continue to attract attention to this important family of antimicrobial peptides.
----
Human Antimicrobial Peptides as Therapeutics for Viral Infections
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722670/
2. Defensins
2.1. Expression
Highly abundant and widely distributed, defensins modulate immune responses thereby playing a central role in innate immunity [6,7,8]. Defensins are classified into three subgroups: a, ß and ?. Although humans do not produce functional members of the ?-defensin family of AMPs, expression of ?-defensin mRNA has been observed in humans. The ?-defensin mRNA contains a pre-mature stop codon which prevents translation; however, functional ?-defensins are present in non-human primates [9]. To date, six a-defensin and 31 ß-defensin peptides have been identified in various species [9]. Originally isolated from neutrophils, four of the six distinct a-defensins are termed human neutrophil peptides (HNP-1 through 4). They are also produced by myeloid-lineage cells such as macrophages, natural killer (NK) cells and some classes of T and B-cells. a-defensins 5 (HD5) and 6 (HD6) are expressed in epithelial cells in the small intestine [6,8,9,10]. The ß-defensin family of AMPs is commonly expressed in birds and mammals. In humans, three ß-defensins (HBD-1 through 3) have been fully characterized and a fourth, HBD-4, was recently identified. ß-defensins are primarily expressed by epithelial cells and keratinocytes, but can also be produced by neutrophils, macrophages, mast cells, NK cells, dendritic cells, and lymphocytes [6,7,8,10]. Current data suggest a functional redundancy when comparing the efficacy of a and ß defensins against various pathogens [11].
Defensins are defined by the presence of a conserved spacing pattern comprised of cysteine residues, which is critical for the efficacy of their cationic antimicrobial properties [9,12]. Human a-defensins are composed of 29 to 34 amino acids with an overall positive charge [9,12,13]. Defensins exhibit a characteristic ß-sheet structure with a distinctive six-cysteine motif for which stabilization is a consequence of the presence of three intramolecular disulfide bonds. The a-defensins are synthesized as pre-propeptides consisting of a N-terminal signal sequence, an anionic pro-peptide, and a C-terminal mature peptide comprised of approximately 30 amino acids. HNP1, HNP2, and HNP3 are synthesized by promyelocytes and stored in primary neutrophil granules as mature peptides [10]. In contrast, ß-defensins have a short N-terminal pro-region and can retain antimicrobial activity in full-length form, and; therefore, do not require N-terminal processing to be fully active [14]. They are synthesized in epithelial compartments and can range from 38 to 42 amino acids in length.
2.2. Antiviral Activity of Defensins
The antiviral activity of defensins was first reported in 1986 [10]. Since then, defensins have demonstrated protection against human immunodeficiency virus (HIV), influenza A virus (IAV), human adenovirus (HAdV), severe acute respiratory syndrome coronavirus (SARSC), papillomavirus (HPV), respiratory syncytial virus (RSV), and herpes simplex virus (HSV) [5,10,15,16,17,18]. Recent studies have focused on elucidating the multiple mechanisms associated with defensins’ antiviral activity (Table 1). Defensins can block viral infection through direct action on virus particles or interfere indirectly at various stages of the viral life cycle [10,18]. Available data suggest antiviral activity occurs predominantly at viral entry steps; however, antiviral effects at other stages of infection have also been reported, particularly affecting viral trafficking within infected cells [19]. Defensins can also modify the innate immune response to viral infections, including: modulation of T-cells, macrophage and dendritic cells recruitment to sites of infection, wound healing and angiogenesis, differentiation and maturation of dendritic cells, induction of the production of pro-inflammatory cytokines by macrophages, mast cells, and keratinocytes, and regulation of cell death pathways [9]. For example, HBD-3 can suppress activation of the caspase cascade to prevent apoptosis in infected cells [20]. Similarly, the concentration of HNPs released into the microenvironment upon activation of neutrophils during inflammation exerts a differential effect on cytokine production in activated monocytes [19]. HNP concentrations of 1 to 10 nM can upregulate the expression of tumor necrosis factor a (TNF-a) and interleukin-1ß (IL-1ß), whereas concentrations of 10 to 100 µM are cytotoxic to monocytes.
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10. Conclusions
Progress has been made in the last decade to elucidate the mechanisms of action of various AMPs. The primary mechanism of AMP-mediated antiviral activity has been attributed to direct interference with, and destabilization of, viral envelopes. However, AMPs have also demonstrated selective immune modulation. Antiviral activity against both enveloped and non-enveloped viruses has been reported with the latter hinting at the presence of undiscovered activities of AMPs, in addition to the known direct interaction with viral envelopes. Indeed, antiviral activity has also been reported at post entry steps affecting later stages in the viral life cycle, such as genome replication and viral protein trafficking. Additionally, studies have demonstrated that AMP treatment prior to viral infection results in peptide retention and internalization by cells which may reflect a more robust response to viruses compared to other potential therapeutics in development. Additionally, post-infection treatments have been reported to exhibit antiviral activity; however, to a lesser extent to that of treatments prior to infection. Nonetheless, these treatments play a role in altering viral replication and assembly as well as a role in accelerating immune activation or suppression. Hence, AMPs can directly impact viral infections or can modulate host processes that ultimately impact viral replication negatively. AMPs have been reported to drive interferon ß (IFNß) signaling, contributing to the induction of an antiviral state in susceptible cells. This dual functionality of AMPs is advantageous as they can be used as a prophylactic and/or as part of post-exposure antiviral measures. In vulnerable individuals, prophylactic expression of AMPs has the potential to become a preventative strategy against viral infections, especially during emerging pandemics. In addition, the simplicity of AMPs makes the development of synthetic peptide analogues a cost-effective measure to treat established viral infections. AMPs and their synthetic derivatives are a promising avenue to yield new strategies to control and treat a wide range of viral diseases but their application is still at the preliminary stages. Therefore, further research is warranted to understand AMP antiviral activity both in vivo and in vitro and to determine underlying mechanisms involved in AMP-mediated immune modulation for clinical applications.
----
Defensins and Viral Infection: Dispelling Common Misconceptions
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004186
lol, TIAB, but not so much - getting BRI in front of virologists, BARDA, is absolutely the right thing to do and time well spent, not just in inc Viz to company/BRI-platform, but who knows if Uncle Sam, others, wake up to potential. academics and rookie research geeks like me have long BRI-(HDP-M)believed. maybe it's our time in the sickening face of Cvirus. lots of lit out there on Defensins/AMP (esp synthesized, optimized ones that overcome the dev challenges of natural Defensins/AMPs). just go to google scholar. a few lifts below i did while sipping coffee. if BRI, leading Swiss Army Knife in Clinical Dev, shows even miniminal anti-viral activity, via the MTAs, and more imptly against COVID-19, well, let's see how busy Leo's phone becomes, inbound. could easily see NIH backing to do a single-dose IV trial to see if helps w sickest patients, with BRI vaccine a longer a play. let's get those MTAs executed and see what BRI might be able to do.
some scientific-based BRI-believing (BRI-Be-Liv-ing) reading before your shift in the ED, good doctor
----
Defensins in innate immunity
https://journals.lww.com/co-hematology/Abstract/2014/01000/Defensins_in_innate_immunity.8.aspx
Summary
Defensins are the ‘Swiss army knife’ in innate immunity against microbial pathogens. Their modes of action are often reminiscent of the story of ‘The Blind Men and the Elephant’. The functional diversity and mechanistic complexity, as well as therapeutic potential of defensins, will continue to attract attention to this important family of antimicrobial peptides.
----
Human Antimicrobial Peptides as Therapeutics for Viral Infections
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722670/
2. Defensins
2.1. Expression
Highly abundant and widely distributed, defensins modulate immune responses thereby playing a central role in innate immunity [6,7,8]. Defensins are classified into three subgroups: a, ß and ?. Although humans do not produce functional members of the ?-defensin family of AMPs, expression of ?-defensin mRNA has been observed in humans. The ?-defensin mRNA contains a pre-mature stop codon which prevents translation; however, functional ?-defensins are present in non-human primates [9]. To date, six a-defensin and 31 ß-defensin peptides have been identified in various species [9]. Originally isolated from neutrophils, four of the six distinct a-defensins are termed human neutrophil peptides (HNP-1 through 4). They are also produced by myeloid-lineage cells such as macrophages, natural killer (NK) cells and some classes of T and B-cells. a-defensins 5 (HD5) and 6 (HD6) are expressed in epithelial cells in the small intestine [6,8,9,10]. The ß-defensin family of AMPs is commonly expressed in birds and mammals. In humans, three ß-defensins (HBD-1 through 3) have been fully characterized and a fourth, HBD-4, was recently identified. ß-defensins are primarily expressed by epithelial cells and keratinocytes, but can also be produced by neutrophils, macrophages, mast cells, NK cells, dendritic cells, and lymphocytes [6,7,8,10]. Current data suggest a functional redundancy when comparing the efficacy of a and ß defensins against various pathogens [11].
Defensins are defined by the presence of a conserved spacing pattern comprised of cysteine residues, which is critical for the efficacy of their cationic antimicrobial properties [9,12]. Human a-defensins are composed of 29 to 34 amino acids with an overall positive charge [9,12,13]. Defensins exhibit a characteristic ß-sheet structure with a distinctive six-cysteine motif for which stabilization is a consequence of the presence of three intramolecular disulfide bonds. The a-defensins are synthesized as pre-propeptides consisting of a N-terminal signal sequence, an anionic pro-peptide, and a C-terminal mature peptide comprised of approximately 30 amino acids. HNP1, HNP2, and HNP3 are synthesized by promyelocytes and stored in primary neutrophil granules as mature peptides [10]. In contrast, ß-defensins have a short N-terminal pro-region and can retain antimicrobial activity in full-length form, and; therefore, do not require N-terminal processing to be fully active [14]. They are synthesized in epithelial compartments and can range from 38 to 42 amino acids in length.
2.2. Antiviral Activity of Defensins
The antiviral activity of defensins was first reported in 1986 [10]. Since then, defensins have demonstrated protection against human immunodeficiency virus (HIV), influenza A virus (IAV), human adenovirus (HAdV), severe acute respiratory syndrome coronavirus (SARSC), papillomavirus (HPV), respiratory syncytial virus (RSV), and herpes simplex virus (HSV) [5,10,15,16,17,18]. Recent studies have focused on elucidating the multiple mechanisms associated with defensins’ antiviral activity (Table 1). Defensins can block viral infection through direct action on virus particles or interfere indirectly at various stages of the viral life cycle [10,18]. Available data suggest antiviral activity occurs predominantly at viral entry steps; however, antiviral effects at other stages of infection have also been reported, particularly affecting viral trafficking within infected cells [19]. Defensins can also modify the innate immune response to viral infections, including: modulation of T-cells, macrophage and dendritic cells recruitment to sites of infection, wound healing and angiogenesis, differentiation and maturation of dendritic cells, induction of the production of pro-inflammatory cytokines by macrophages, mast cells, and keratinocytes, and regulation of cell death pathways [9]. For example, HBD-3 can suppress activation of the caspase cascade to prevent apoptosis in infected cells [20]. Similarly, the concentration of HNPs released into the microenvironment upon activation of neutrophils during inflammation exerts a differential effect on cytokine production in activated monocytes [19]. HNP concentrations of 1 to 10 nM can upregulate the expression of tumor necrosis factor a (TNF-a) and interleukin-1ß (IL-1ß), whereas concentrations of 10 to 100 µM are cytotoxic to monocytes.
--
10. Conclusions
Progress has been made in the last decade to elucidate the mechanisms of action of various AMPs. The primary mechanism of AMP-mediated antiviral activity has been attributed to direct interference with, and destabilization of, viral envelopes. However, AMPs have also demonstrated selective immune modulation. Antiviral activity against both enveloped and non-enveloped viruses has been reported with the latter hinting at the presence of undiscovered activities of AMPs, in addition to the known direct interaction with viral envelopes. Indeed, antiviral activity has also been reported at post entry steps affecting later stages in the viral life cycle, such as genome replication and viral protein trafficking. Additionally, studies have demonstrated that AMP treatment prior to viral infection results in peptide retention and internalization by cells which may reflect a more robust response to viruses compared to other potential therapeutics in development. Additionally, post-infection treatments have been reported to exhibit antiviral activity; however, to a lesser extent to that of treatments prior to infection. Nonetheless, these treatments play a role in altering viral replication and assembly as well as a role in accelerating immune activation or suppression. Hence, AMPs can directly impact viral infections or can modulate host processes that ultimately impact viral replication negatively. AMPs have been reported to drive interferon ß (IFNß) signaling, contributing to the induction of an antiviral state in susceptible cells. This dual functionality of AMPs is advantageous as they can be used as a prophylactic and/or as part of post-exposure antiviral measures. In vulnerable individuals, prophylactic expression of AMPs has the potential to become a preventative strategy against viral infections, especially during emerging pandemics. In addition, the simplicity of AMPs makes the development of synthetic peptide analogues a cost-effective measure to treat established viral infections. AMPs and their synthetic derivatives are a promising avenue to yield new strategies to control and treat a wide range of viral diseases but their application is still at the preliminary stages. Therefore, further research is warranted to understand AMP antiviral activity both in vivo and in vitro and to determine underlying mechanisms involved in AMP-mediated immune modulation for clinical applications.
----
Defensins and Viral Infection: Dispelling Common Misconceptions
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004186
