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Sigalov A.B.,Signablok, Inc.
Progress in Biophysics and Molecular Biology | Year: 2011

The classical protein structure-function paradigm has been challenged by the emergence of intrinsically disordered proteins (IDPs), the proteins that do not adopt well-defined three-dimensional structures under physiological conditions. This development was accompanied by the introduction of a " coupled binding and folding" paradigm that suggests folding of IDPs upon binding to their partners. However, our recent studies challenge this general view by revealing a novel, previously unrecognized phenomenon - uncoupled binding and folding. This biologically important mechanism is characteristic of members of a new family of IDPs involved in immune signaling and underlies their unusual properties including: (1) specific homodimerization, (2) the lack of folding upon binding to a well-folded protein, another IDP molecule, or to lipid bilayer membranes, and (3) the " scissors-cut paradox" . The third phenomenon occurs in diverse IDP interactions and suggests that properties of IDP fragments are not necessarily additive in the context of the entire protein. The " no disorder-to-order transition" type of binding is distinct from known IDP interactions and is characterized by an unprecedented observation of the lack of chemical shift and peak intensity changes in multidimensional NMR spectra, a fingerprint of proteins, upon complex formation. Here, I focus on those interactions of IDPs with diverse biological partners where the binding phase driven by electrostatic interactions is not be necessarily followed by the hydrophobic folding phase. I also review new multidisciplinary knowledge about immune signaling-related IDPs and show how it expands our understanding of cell function with multiple applications in biology and medicine. © 2011 Elsevier Ltd.


Triggering receptor expressed on myeloid cells-1 (TREM-1) amplifies the inflammatory response and plays a role in cancer and sepsis. Inhibition of TREM-1 by short hairpin RNA (shRNA) in macrophages suppresses cancer cell invasion in vitro. In the clinical setting, high levels of TREM-1 expression on tumor-associated macrophages are associated with cancer recurrence and poor survival of patients with non-small cell lung cancer (NSCLC). TREM-1 upregulation on peritoneal neutrophils has been found in human sepsis patients and in mice with experimental lipopolysaccharide (LPS)-induced septic shock. However, the precise function of TREM-1 and the nature of its ligand are not yet known. In this study, we used the signaling chain homooligomerization (SCHOOL) model of immune signaling to design a novel, ligand-independent peptide-based TREM-1 inhibitor and demonstrated that this peptide specifically silences TREM-1 signaling in vitro and in vivo. Utilizing two human lung tumor xenograft nude mouse models (H292 and A549) and mice with LPS-induced sepsis, we show for the first time that blockade of TREM-1 function using non-toxic and non-immunogenic SCHOOL peptide inhibitors: 1) delays tumor growth in xenograft models of human NSCLC, 2) prolongs survival of mice with LPS-induced septic shock, and 3) substantially decreases cytokine production in vitro and in vivo. In addition, targeted delivery of SCHOOL peptides to macrophages utilizing lipoprotein-mimicking nanoparticles significantly increased peptide half-life and dosage efficacy. Together, the results suggest that ligand-independent modulation of TREM-1 function using small synthetic peptides might be a suitable treatment for sepsis and NSCLC and possibly other types of inflammation- associated disorders. © 2014 Elsevier B.V. All rights reserved.


Sigalov A.B.,Signablok, Inc.
Contrast Media and Molecular Imaging | Year: 2014

Magnetic resonance imaging (MRI) of macrophages in atherosclerosis requires the use of contrast-enhancing agents. Reconstituted lipoprotein particles that mimic native high-density lipoproteins (HDL) are a versatile delivery platform for Gd-based contrast agents (GBCA) but require targeting moieties to direct the particles to macrophages. In this study, a naturally occurring methionine oxidation in the major HDL protein, apolipoprotein (apo) A-I, was exploited as a novel way to target HDL to macrophages. We also tested if fully functional GBCA-HDL can be generated using synthetic apo A-I peptides. The fluorescence and MRI studies reveal that specific oxidation of apo A-I or its peptides increases the in vitro macrophage uptake of GBCA-HDL by 2-3 times. The in vivo imaging studies using an apo E-deficient mouse model of atherosclerosis and a 3.0T MRI system demonstrate that this modification significantly improves atherosclerotic plaque detection using GBCA-HDL. At 24h post-injection of 0.05mmol Gd kg-1 GBCA-HDL containing oxidized apo A-I or its peptides, the atherosclerotic wall/muscle normalized enhancement ratios were 90 and 120%, respectively, while those of GBCA-HDL containing their unmodified counterparts were 35 and 45%, respectively. Confocal fluorescence microscopy confirms the accumulation of GBCA-HDL containing oxidized apo A-I or its peptides in intraplaque macrophages. Together, the results of this study confirm the hypothesis that specific oxidation of apo A-I targets GBCA-HDL to macrophages in vitro and in vivo. Furthermore, our observation that synthetic peptides can functionally replace the native apo A-I protein in HDL further encourages the development of these contrast agents for macrophage imaging. © 2014 John Wiley & Sons, Ltd.


Patent
Signablok, Inc. | Date: 2013-07-12

Peptides are provided consisting of L- and/or D-amino acids and combinations thereof, which affect myeloid cells by action on the triggering receptors expressed on myeloid cells (TREMs), including TREM-1 and TREM-2. The peptides act on the TREM/DAP-12 signaling complex. Also provided are lipid and sugar conjugated peptides comprising L- or D-amino acids. A method is provided of designing the peptides and lipid- and/or sugar-conjugated peptides comprising L- or D-amino acids. The disclosure relates to the therapy of various myeloid cell-related disease states involving the use of these peptides and compounds. The peptides and compounds are useful in the treatment and/or prevention of a disease or condition where myeloid cells are involved or recruited. The peptides of the present invention also are useful in the production of medical devices comprising peptide matrices (for example, medical implants and implantable devices).


Patent
Signablok, Inc. | Date: 2011-02-16

The disclosure provides compounds and compositions, and methods of using these compounds and compositions, for the targeted delivery of therapeutic agents. In one embodiment, these compositions are used for the tumor-targeted delivery of chemotherapeutic agents useful for treating cancer.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 223.44K | Year: 2016

DESCRIPTION provided by applicant Alcoholic liver disease ALD affects millions of people globally and often leads to fibrosis and cirrhosis With a total of deaths in of which were alcohol related liver cirrhosis is the th leading cause of death in the United States and costs society more than $ billion annually Despite this tremendous societal and economic burden no approved therapeutics for ALD are available Current treatments include corticosteroids immunosuppressants and antioxidants They all have multiple shortcomings including a high level of serious side effects and insufficient efficacy This highlights the need for new liver specific treatments Alcohol mediated activation of Kupffer cells resident macrophages of the liver results in proinflammatory cytokine production and ultimately liver damage This suggests Kupffer cell activation as a promising target for prevention and treatment of ALD Triggering receptor expressed on myeloid cells TREM an inflammation amplifier is involved in a variety of inflammation associated diseases Blockade of TREM attenuates inflammation and improves outcome in mice with sepsis cancer rheumatoid arthritis and other inflammatory disorders Recently deficiency of TREM expressed by Kupffer cells has been shown to attenuate Kupffer cell activation resulting in diminished chemically induced liver injury We hypothesize that inhibition of TREM can be used to prevent and treat ALD This is rationalized by the fact that TREM is upregulated under inflammatory conditions and induces proinflammatory cytokines expression Current approaches to TREM suggest to block binding of ligand to TREM The true nature of the TREM ligand is not yet known highly increasing the risk of failure of these approaches in clinical development Recently we demonstrated in animal models that a novel peptide inhibitor of TREM suppresses inflammatory response and ameliorates cancer and sepsis The peptide employs a ligand independent mechanism of action and is non toxic The long term objective of the proposed project is to develop a novel TREM targeted approach to prevention and treatment of ALD Phase I specific aims are to test TREM inhibitors in Kupffer cells alone and co cultured with hepatocytes and test TREM inhibitors in a mouse model of alcoholic liver disease In order to increase peptide solubility bioavailability and targeting to sites of inflammation we will utilize SignaBlokandapos s proprietary nanosystem for macrophage specific delivery We will synthesize nanoformulations that contain TREM inhibitory peptide and assess their inhibitory activity in vitro using rat Kupffer cells cultured alone or co cultured wih rat hepatocytes We will vary the composition of nanoparticles and choose the optimal formulation based upon peptide content and inhibitory activity In order to assess therapeutic efficacy of the optimal formulation in vivo we will use a mouse model of ALD In order to evaluate liver damage we will measure serum alanine aminotransferase in the serum and perform thorough histopathological analysis of the liver sections We will also analyze proinflammatory cytokines in the serum and in the liver It is anticipated that the Phase I study will identify novel first in class targeted agents that will provide a powerful platform for prevention and treatment of ALD If successful the Phase I will be followed in the Phase II by toxicology absorption disposition metabolism excretion ADME pharmacology and chemistry manufacturing control CMC studies filing an Investigational New Drug IND application with the US Food and Drug Administration FDA and subsequent evaluation in humans Importantly the macrophage specific nanoparticles is a versatile multifunctional delivery platform Thus successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable for a targeted combination therapy of ALD PUBLIC HEALTH RELEVANCE Alcoholic liver disease ALD affects over million people worldwide with more than deaths per year attributed to ALD in the United States Currently there is no specific medical treatment for ALD The proposed research will result in the development of novel mechanism based agents that could substantially improve prevention and treatment of ALD allowing for reduction of alcohol related morbidity and mortality


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 219.94K | Year: 2015

DESCRIPTION provided by applicant Carcinoma of the pancreas or pancreatic cancer PC is the fourth leading cause of cancer related death in the United States According to the American Cancer Society new cases and deaths are expected in Despite advances in therapy the year survival rate is less than Current treatments of PC include surgery radiation therapy chemotherapy and immunotherapy but they all only slightly prolong survival or relieve symptoms in patients with PC The limitations in efficacy of available treatments highlight the need for new treatments Pancreatic inflammation is known to increase the risk of PC High macrophage infiltration into the tumor mass correlates with the promotion of tumor growth and metastasis development As found recently triggering receptor expressed on myeloid cells TREM an inflammation amplifier plays a role in PC progression Expression of TREM on myeloid cells including tumor associated macrophages TAMs in patients with PC is upregulated and correlates to disease severity We hypothesize that TREM inhibition can improve survival of PC patients Current approaches to TREM suggest to block binding of ligand to TREM The true nature of the TREM ligand is not yet known highly increasing the risk of failure of these approaches in clinical development The long term objective of the proposed project is to develop a novel ligand independent approach to a TREM targeted treatment of PC The major goal of the Phase I study is to demonstrate that specific inactivation of TREM with novel inhibitory peptides suppresses PC tumor progression in animal model system and improves survival Phase I specific aims are to generate and characterize injectable formulations of TREM inhibitory peptides with different half lives and test the TREM inhibitory peptide formulations in a mouse model of PC The peptides will be designed using SignaBlokandapos s proprietary model of TREM signaling These non toxic peptides employ novel ligand independent mechanisms of action and are anticipated to have less severe side effects In order to increase peptide solubility bioavailability and targeting to TAMs we will utilize SignaBlokandapos s proprietary nanosystem for macrophage targeted delivery of water insoluble and poorly water soluble drugs We will use a BxPC xenograft mouse model of PC to test the ability of the peptides in free and particulate forms to inhibit cancer progression and promote survival It is anticipated that the proposed research will identify novel anticancer lead compounds that will set the stage for the development of new targeted therapies of PC thereby leading to a higher survival rate of the patients If successful the Phase I will be followed in te Phase II by toxicology absorption disposition metabolism excretion ADME pharmacology and chemistry manufacturing control CMC studies filing an Investigational New Drug IND application with the US Food and Drug Administration FDA and subsequent evaluation in humans Importantly TREM may play a role in the progression of not only PC but also other tumors Thus successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable to a variety of tumors PUBLIC HEALTH RELEVANCE Pancreatic cancer is the fourth leading cause of cancer related death in the United States and the year survival rate is less than Current treatments are substantially ineffective and only slightly prolong survival or relieve symptoms in the cancer patients The proposed research is expected to result in the development of novel anticancer therapeutics that could substantially improve treatment of this type of cancer thereby leading to a higher survival rate of the patients


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 221.83K | Year: 2012

DESCRIPTION (provided by applicant): Despite advances in cardiovascular care, atherosclerosis remains the leading cause of mortality in the United States and worldwide. A vast majority of cardiovascular events such as stroke or myocardial infarction resultfrom rupture or erosion of vulnerable atherosclerotic plaques. These plaques are characterized by high and active macrophage content. Accurate in vivo tracking of plaque vulnerability and progression using non-invasive imaging approaches allows early identification of high-risk patients as well as facilitates early intervention decision-making process and monitoring of the effectiveness of interventions. However, current imaging modalities including magnetic resonance (MR) imaging characterize anatomic andstructural features of the plaque rather than its content. Contrast agents such as gadolinium-based contrast agents (GBCAs) are often used in cardiovascular MR imaging to enhance contrast between tissues. Macrophage-specific delivery of GBCAs will allow early detection of vulnerable plaques and risk stratification of vulnerable patients. This wil also minimize the GBCA dose, thus diminishing the risk of nephrogenic systemic fibrosis, a major adverse consequence of GBCAs that may lead to disability or death. Recently, high density lipoproteins (HDLs) were suggested as delivery nanocarriers for GBCAs. We hypothesize that oxidative modification of apolipoprotein (apo) A-I, the major protein constituent of HDL, can be used to direct GBCA-carrying HDL (GBCA-HDL)to macrophage-rich plaques. This is rationalized by the fact that this modification occurs in vivo and converts HDL into a substrate for macrophages. Thus, it may enhance intraplaque macrophage uptake of HDL. The long-term objective of the proposed project is to develop a novel approach to early detection and evaluation of vulnerable plaques. The major goal of the Phase I study is to demonstrate that modification of apo A-I in HDL-based MR imaging agents increases the detection of intraplaque macrophages in animal model system. Phase I specific aims are: 1) generate and characterize GBCA-HDL nanoformulations that contain modified apo A-I, and 2) test the optimal GBCA-HDL formulation in a mouse model of atherosclerosis. We will synthesize GBCA-HDL particlesthat contain modified apo A-I, characterize them and assess macrophage uptake in vitro. We will vary the GBCA:lipid:apo A-I ratios and choose the optimal formulation based upon maximum Gd content and highest macrophage uptake. We will use apo E-knockout mouse model to assess MR efficacy of the optimal formulation in plaque imaging in vivo. It is anticipated that the Phase study will identify novel MR contrast agents that will provide a powerful platform for imaging of atherosclerosis. The Phase I data willbe used to improve this technology in a Phase II program. Importantly, not only imaging but also therapeutic agents can be incorporated into the proposed platform. Thus, successful completion of Phase I will provide the proof of concept for the development of new multifunctional nanoformulations for targeted delivery of diagnostics and therapeutics. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the major cause of cardiovascular disease, the number one leading cause of death worldwide. The proposed research will result in the development of novel imaging techniques that could substantially improve early diagnosis and treatment of atherosclerosis, allowing for diagnosis before symptoms occur, identification of those individuals with higher risk, and for monitoring response to treatment.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 223.01K | Year: 2014

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that causes chronic inflammation of the joints. RA affects about 1.5 million Americans and costs society more than 40 billion each year. Despite advances in therapy, RA has no cure. Current treatments of RA include non-steroidal anti- inflammatory drugs, corticosteroids, and disease modifying anti-rheumatic drugs (DMARDs). They all have multiple shortcomings including a high level of serious side effects and insufficient efficacy. Methotrexate (MTX), a folate antagonist that blocks folic acid activity, is the most widely used non-biologic DMARD. However, its significant toxicity which is usually related to the dose taken drastically limits its clinical use and is the most common cause of discontinuing MTX therapy. Biologic DMARDs include tumor necrosis factor (TNF) blockers such as Humira. TNF blockers may cause serious side effects such as infections and malignancies. This highlights the need for


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 221.74K | Year: 2012

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) affects over 222,000 Americans annually. Despite advances in therapy, the 5-year survival rate is as low as 15%. Current treatments of NSCLC include cytotoxic chemotherapy and targeted biologic therapies. They all have multiple shortcomings including only a modest increase in survival and significant toxicity to the patient. The limitations in efficacy and safety associated with availabe treatments for NSCLC highlight the need for newtreatments. As found recently, triggering receptor expressed on myeloid cells (TREM-1) plays a role in NSCLC progression. Inhibition of TREM-1 by short hairpin RNA (shRNA) in macrophages is shown to suppress cancer cell invasion. In clinical setting, the 4-year survival rate in patients with low expression of TREM-1 on tumor-associated macrophages (TAMs) is 60%, compared with 20% in those with high expression. We hypothesize that TREM-1 inhibition can improve survival of NSCLC patients. The long-term objective of the proposed project is to develop a novel approach to targeted treatment of NSCLC. The major goal of the Phase I study is to demonstrate that specific inactivation of TREM-1 with novel inhibitory peptides suppresses tumor progression in animal model system and improves survival. Phase I specific aims are to: 1) generate and characterize injectable formulations of TREM-1 inhibitory peptides, and 2) test the TREM-1 inhibitory peptides in a mouse model of NSCLC. The peptides will be designed using SignaBlok's proprietary model of TREM-1 signaling. These peptides employ novel, ligand-independent mechanisms of action and are anticipated to have less severe side effects. In order to increase peptide solubility, bioavailability and targeting to TAMs, we will utilize SignaBlok's proprietary nanosystem for macrophage-targeted delivery of water insoluble and poorly water soluble drugs. We will use a NCI-H292 xenograft mouse model of NSCLC to test the ability of the peptides in free and particulate forms to inhibit cancer progression and promote survival. It is anticipated that the proposed research will identify novel anticancer lead compounds that will set the stage for the development of new targeted therapies of NSCLC, thereby leading to a higher survival rate of the patients. The Phase I data will be used to further improve this technology in a Phase II program. Importantly, TREM-1 may play a role in the progression of not only NSCLC but also other tumors. Thus, successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable to a variety of tumors. PUBLIC HEALTH RELEVANCE: Non-small cell lung cancer kills more patients than breast, colon, and prostate cancer combined, and the 5- year survival rate is 15%.Current treatment has multiple shortcomings including only a modest increase in survival and significant toxicity to the patient. The proposed research is expected to result in the development of novel anticancer therapeutics that could substantially improve treatment of this type of cancer, thereby leading to a higher survival rate of the patients.

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