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April 2008 - present
Publications
Publications (86)
Ferroportin (Fpn) is the only known iron exporter in humans and is essential for maintaining iron homeostasis. Fpn activity is suppressed by hepcidin, an endogenous peptide hormone, which inhibits iron export and promotes endocytosis of Fpn. Hepcidin deficiency leads to hemochromatosis and iron-loading anemia. Previous studies have shown that small...
Ferroportin (Fpn) is the only known iron exporter in humans and is essential for maintaining iron homeostasis. Fpn activity is suppressed by hepcidin, an endogenous peptide hormone, which inhibits iron export and promotes endocytosis of Fpn. Hepcidin deficiency leads to hemochromatosis and iron-loading anemia. Previous studies have shown that small...
We previously reported several vignettes on types and classes of drugs able to mitigate acute and, in at least one case, late radiation syndromes in mice. Most of these had emerged from high throughput screening (HTS) of bioactive and chemical drug libraries using ionizing radiation-induced lymphocytic apoptosis as a readout. Here we report the ful...
Iron disorders are associated with adverse pregnancy outcomes, yet iron homeostatic mechanisms during pregnancy are poorly understood. In humans and rodents, the iron-regulatory hormone hepcidin is profoundly decreased in pregnant mothers, which is thought to ensure adequate iron availability for transfer across placenta. However, the fetal liver a...
Zika virus (ZIKV) has become a public health concern worldwide due to its association with congenital abnormalities and neurological diseases. To date, no effective vaccines or antiviral drugs have been approved for the treatment of ZIKV infection, and new inexpensive therapeutic options are urgently needed. In this study, we have used an in vitro...
A small group of lipid-conjugated Smac mimetics was synthesized to probe the influence of the position of lipidation on overall anti-cancer activity. Specifically, new compounds were modified with lipid(s)in position 3 and C-terminus. Previously described position 2 lipidated analog M11 was also synthesized. The resulting mini library of Smacs lipi...
Zika Virus (ZIKV), a member of the Flaviviridae family of viruses, has recently led to major epidemics in South American countries and has been reported in several other countries as well. ZIKV is the cause of microcephaly and other developmental neuroimmunopathologies in fetuses of pregnant women and Guillain‐Barre Syndrome in adults, and to date,...
Abundant attention has focused on synaptotagmin's C2 domains, but less is known about the structure and function of its other regions. Here, we synthesized the N-acetylated, C-end amidated and Cys-palmitated peptide (VLTCCFCICK KCLFKKKNKK K) which includes the fatty acylated cysteine residues in the membrane-affiliated domain of synaptotagmin-1. Fo...
Iron is an essential micronutrient for most microbes and their hosts. Mammalian hosts respond to infection by inducing the iron-regulatory hormone hepcidin, which causes iron sequestration and a rapid decrease in plasma and extracellular iron concentration (hypoferremia). Previous studies showed that hepcidin regulation of iron is essential for pro...
Zika virus (ZIKV) has recently been the cause of major epidemics in South American countries especially Brazil. ZIKV has been identified as the cause of microcephaly in the fetuses of pregnant women and the Guillain‐Barre Syndrome, and to date, no therapeutics or vaccines are available against ZIKV infection. Previously, we reported the anti‐ZIKV a...
The rate of Zika virus (ZIKV) infection has been increasing since the original 2014 re‐emergence of the virus in Brazil, and the World Health Organization has warned against potential ZIKV epidemics. Furthermore, ZIKV, a flavivirus family member, has been identified as the cause of microcephaly and other developmental neuroimmunopathologies in fetu...
Enveloped viruses enter cells by using their fusion proteins to merge the virus lipid envelope and the cell membrane. While crystal structures of the water-soluble ectodomains of many viral fusion proteins have been determined, the structure and assembly of the C-terminal transmembrane domain (TMD) remains poorly understood. Here we use solid-state...
The recent re-emergence of Zika virus (ZIKV), a member of the Flaviviridae family, has become a global emergency and a serious public health threat worldwide. ZIKV infection causes severe neuroimmunopathology and is particularly harmful to the developing fetuses of infected pregnant women causing various developmental abnormalities. Currently, ther...
Background & aims:
Little is known about the signaling pathways that initiate and promote acute pancreatitis (AP). The pathogenesis of AP has been associated with abnormal increases in cytosolic Ca(2+), mitochondrial dysfunction, impaired autophagy, and endoplasmic reticulum (ER) stress. We analyzed the mechanisms of these dysfunctions and their r...
Our ability to use ionizing radiation as an energy source, as a therapeutic agent, and, unfortunately, as a weapon, has evolved tremendously over the past 120 years, yet our tool box to handle the consequences of accidental and unwanted radiation exposure remains very limited. We have identified a novel group of small molecule compounds with a 4-ni...
Key Points
In mouse models, hepcidin participates in innate immunity by controlling NTBI. NTBI-dependent infections can be treated with hepcidin agonists in mouse models of hereditary hemochromatosis or parenteral iron overload.
Iron is both an essential and a potentially toxic element and its systemic homeostasis is controlled by the iron-hormone hepcidin. Hepcidin binds to the cellular iron exporter ferroportin, causes its degradation and thereby diminishes iron uptake from the intestine and the release of iron from macrophages. Given that hepcidin-resistant ferroportin...
A small library of anticancer, cell-permeating, stapled peptides based on potent dual-specific antagonist of p53–MDM2/MDMX interactions, PMI-N8A, was synthesized, characterized and screened for anticancer activity against human colorectal cancer cell line, HCT-116. Employed synthetic modifications included: S-alkylation-based stapling, point mutati...
The human molecular chaperones heat shock protein 70 (Hsp70) and heat shock cognate protein 70 (Hsc70) bind to the hepatitis C viral nonstructural protein 5A (NS5A) and regulate its activity. Specifically, Hsp70 is involved in NS5A-augmented internal ribosomal entry site (IRES)-mediated translation of the viral genome, whilst Hsc70 appears to be pr...
The tetrameric thyroxine transport protein transthyretin (TTR) forms amyloid fibrils upon dissociation and monomer unfolding.
The aggregation of transthyretin has been reported as the cause of the life-threatening transthyretin amyloidosis. The standard
treatment of familial cases of TTR amyloidosis has been liver transplantation. Although aggregat...
Hereditary hemochromatosis, an iron overload disease caused by a deficiency in the iron-regulatory hormone hepcidin, is associated with lethal infections by siderophilic bacteria. To elucidate the mechanisms of this susceptibility, we infected wild-type and hepcidin-deficient mice with the siderophilic bacterium Vibrio vulnificus and found that hep...
We previously identified the NS5A/HSP70 binding site to be a hairpin moiety at C-terminus of NS5A domain I and showed a corresponding cyclized polyarginine-tagged synthetic peptide (HCV4) significantly blocks virus production. Here, sequence comparison confirmed five residues to be conserved. Based on NS5A domain I crystal structure, Phe171, Val173...
Background. Surfactant protein C (SP-C; 35 residues) in lungs has a cationic N-terminal domain with two cysteines covalently linked to palmitoyls and a C-terminal region enriched in Val, Leu and Ile. Native SP-C shows high surface activity, due to SP-C inserting in the bilayer with its cationic N-terminus binding to the polar headgroup and its hydr...
Inappropriate production of the iron-regulatory hormone hepcidin contributes to the pathogenesis of common iron disorders. Absolute or relative deficiency of hepcidin causes iron overload in hereditary hemochromatosis and iron-loading anemias. Elevated hepcidin causes iron restriction in inflammatory conditions including autoimmune disease, critica...
Fusion inhibitors are a class of antiretroviral drugs used to prevent entry of HIV into host cells. Many of the fusion inhibitors being developed, including the drug enfuvirtide, are peptides designed to competitively inhibit the viral fusion protein gp41. With the emergence of drug resistance, there is an increased need for effective and unique al...
Since the discovery of human immunodeficiency virus (HIV) as a causative agent of acquired immune deficiency syndrome (AIDS) various strategies were employed to counter its devastating actions. One such concept relies on the prevention of HIV entry into host's "competent" cells by means of compounds known as entry inhibitors. HIV entry inhibitors c...
The deficiency of hepcidin, the hormone that controls iron absorption and its tissue distribution, is the cause of iron overload in nearly all forms of hereditary hemochromatosis and in untransfused iron-loading anemias. In a recent study we reported the development of minihepcidins, small drug-like hepcidin agonists. Here we explore the feasibilit...
We developed a new peptide, natural phytochelatin (PC), which tightly binds to CdSe/ZnS quantum dots' (QDs) surfaces and renders them water-soluble. Coating QDs with this flexible and all-hydrophilic peptide offers high colloidal stability, adds only 0.8-0.9 nm to the radius of the particles (as compared to their original inorganic radius), preserv...
Unlabelled:
NS5A is a key regulator of the hepatitis C virus (HCV) life cycle including RNA replication, assembly, and translation. We and others have shown that NS5A augments HCV internal ribosomal entry site (IRES)-mediated translation. Furthermore, Quercetin treatment and heat shock protein (HSP) 70 knockdown inhibit the NS5A-driven augmentatio...
Non‐structural protein 5A (NS5A) is a key regulator of the hepatitis C virus (HCV) life cycle including RNA replication, assembly and HCV internal ribosome entry site (IRES)‐mediated translation. We have previously identified an NS5A/heat shock protein 70 (HSP70) complex that is important for HCV IRES mediated translation. We have mapped the HSP70...
θ-Defensins are cyclic octadecapeptides found in nonhuman primates whose broad antiviral spectrum includes HIV-1, HSV-1, severe acute respiratory syndrome coronavirus, and influenza A virus (IAV). We previously reported that synthetic θ-defensins called retrocyclins can neutralize and aggregate various strains of IAV and increase IAV uptake by neut...
We investigated the effects of KL₄, a 21-residue amphipathic peptide approximating the overall ratio of positively charged to hydrophobic amino acids in surfactant protein B (SP-B), on the structure and collapse of dipalmitoylphosphatidylcholine and palmitoyl-oleoyl-phosphatidylglycerol monolayers. As reported in prior work on model lung surfactant...
Peptides of the innate immune system provide intriguing templates for designing novel antiviral molecules. θ-defensins are nonhuman primate peptides with broad-spectrum antiviral activities. The activity of these compounds is mediated through interference with viral fusion, and this activity is based upon key structural features. However, two major...
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Mini-hepcidins are synthetic peptide analogues of the hepcidin N-terminus which is crucial for hepcidin interaction with ferroportin. Due to their small size and relative ease of synthesis, mini-hepcidins are better candidates than native hepcidin as therapeutics for the prevention and treatment of iron overload. In our previous studies, the fi...
Secondary structure estimation as measured by FTIR spectroscopy. Relative amounts of α-helix, β-turn, β-sheet, or random (disordered) structures were estimated by Fourier self-deconvolution (GRAMS/AI8, version 8.0, Thermo Electron Corp, Waltham, MA) and area calculations of component peaks calculated with curve fitting software (Igor Pro, version 1...
Differences in experimental outcomes were compared by student t test. P values≤0.05 (95%) were considered to be significant and are indicated in red.
(DOC)
Quantitative analysis of RP-1 on membrane energetics (DiOC5) and membrane permeabilization (PI) in ST, SA and CA. Data are normalized to stained control cell fluorescence and expressed as percent of control (dashed line is equivalent to 100%). Time points: 5, 30 and 60 min. Data shown represent exposure to either ethanol (yellow), CCCP (red) or RP-...
Structure-mechanism relationships are key determinants of host defense peptide efficacy. These relationships are influenced by anatomic, physiologic and microbiologic contexts. Structure-mechanism correlates were assessed for the synthetic peptide RP-1, modeled on microbicidal domains of platelet kinocidins. Antimicrobial efficacies and mechanisms...
Iron overload is the hallmark of hereditary hemochromatosis and a complication of iron-loading anemias such as β-thalassemia. Treatment can be burdensome and have significant side effects, and new therapeutic options are needed. Iron overload in hereditary hemochromatosis and β-thalassemia intermedia is caused by hepcidin deficiency. Although trans...
Many lung cancer treatment regimens include radiotherapy. We sought to improve the efficacy of such treatment by invoking the targeted delivery of a model radiosensitizer (nicotinamide) to malignant tissues. Ephrin receptors (Eph), which are often overexpressed in lung cancers, were selected as the target of our delivery system. Molecular targeting...
Retrocyclins are humanized versions of the θ-defensin peptides expressed by the leukocytes of several nonhuman primates. Previous
studies, performed in serum-free media, determined that retrocyclins 1 (RC1) and RC2 could prevent successful germination
of Bacillus anthracis spores, kill vegetative B. anthracis cells, and inactivate anthrax lethal fa...
The structural basis for the gram selectivity of two disulfide-bonded β-hairpin antimicrobial peptides (AMPs) is investigated using solid-state nuclear magnetic resonance (NMR) spectroscopy. The hexa-arginine PG-1 exhibits potent activities against both gram-positive and gram-negative bacteria, while a mutant of PG-1 with only three cationic residu...
With Figures S1, S2, and S3, and Tables S1 and S2.
(3.70 MB PDF)
Griffithsin, a 121-residue protein isolated from a red algal Griffithsia sp., binds high mannose N-linked glycans of virus surface glycoproteins with extremely high affinity, a property that allows it to prevent the entry of primary isolates and laboratory strains of T- and M-tropic HIV-1. We used the sequence of a portion of griffithsin's sequence...
RC-101 is a congener of the antiretroviral peptide retrocyclin, which we and others have reported is active against clinical HIV-1 isolates from all major clades, does not hemagglutinate, and is non-toxic and non-inflammatory in cervicovaginal cell culture. Herein, film-formulated RC-101 was assessed for its antiviral activity in vitro, safety in v...
The protein transduction domain of HIV-1 TAT, TAT(48-60), is an efficient cell-penetrating peptide (CPP) that diffuses across the lipid membranes of cells despite eight cationic Arg and Lys residues. To understand its mechanism of membrane translocation against the free energy barrier, we have conducted solid-state NMR experiments to determine the...
Analytical data for OxP peptides. Peptide purity was evaluated by matrix-assisted laser desorption ionization spectrometry (MALDI-MS) and by analytical RP-HPLC, using a ProStar 210 HPLC system with a ProStar 325 Dual Wavelength detector set at 220 nm and 280 nm (Varian Inc., Palo Alto, CA). The mobile phases were: Solvent A, 0.1% TFA in water; solv...
Two examples of analytical RP-HPLC profiles and corresponding MS spectra obtained for OxP peptides. Panel A - OxP-5; Panel B - OxP-11D.
(0.13 MB DOC)
Many gram-positive bacteria produce pore-forming exotoxins that contain a highly conserved, 12-residue domain (ECTGLAWEWWRT) that binds cholesterol. This domain is usually flanked N-terminally by arginine and C-terminally by valine. We used this 14-residue sequence as a template to create a small library of peptides that bind cholesterol and other...
The hepcidin‐ferroportin interaction is the central regulatory event in systemic iron homeostasis. To facilitate the understanding of hepcidin structure and to aid the development of useful hepcidin agonists we searched for the minimal structure that would display hepcidin agonist activity. The bioactivity of candidate peptides was assayed by flow...
Surfactant protein B (SP-B; 79 residues) belongs to the saposin protein superfamily, and plays functional roles in lung surfactant. The disulfide cross-linked, N- and C-terminal domains of SP-B have been theoretically predicted to fold as charged, amphipathic helices, suggesting their participation in surfactant activities. Earlier structural studi...
Lung surfactant protein B (SP-B) is required for proper surface activity of pulmonary surfactant. In model lung surfactant lipid systems composed of saturated and unsaturated lipids, the unsaturated lipids are removed from the film at high compression. It is thought that SP-B helps anchor these lipids closely to the monolayer in three-dimensional c...
Amyloid beta-protein (Abeta) self-assembly is linked strongly to Alzheimer's disease. We found that PP-Leu, a tridecapeptide analogue of broad-spectrum antiviral peptides termed theta-defensins, potently inhibits Abeta oligomer and fibril formation. This effect appeared to be mediated through sequestration of the amyloidogenic Abeta peptide in coll...
Many pathogenic gram-positive bacteria release exotoxins that belong to the family of cholesterol-dependent cytolysins. Here, we report that human alpha-defensins HNP-1 to HNP-3 acted in a concentration-dependent manner to protect human red blood cells from the lytic effects of three of these exotoxins: anthrolysin O (ALO), listeriolysin O, and pne...
Antimicrobial host defense peptides (AHDPs) are effective against a wide range of microbes, including viruses. The arteriviral infection caused by porcine reproductive and respiratory syndrome virus (PRRSV) is a devastating pandemic that causes the most economically significant disease of swine. We sought to determine if the expression of AHDPs was...
We have reported that the alpha-defensins human neutrophil peptides (HNP)-1 and HNP-2 neutralize and aggregate influenza A virus (IAV) and promote uptake of IAV by neutrophils. These alpha-defensins were also shown to bind to surfactant protein (SP)-D and reduce its antiviral activity. In this study, we examined retrocyclin (RC)1 and RC2, humanized...
Four of the six human alpha-defensins (human neutrophil peptides 1-3 and human alpha-defensin 5; HD5) have a lectin-like ability to bind glycosylated proteins. Using HD5 as a model, we applied surface plasmon resonance techniques to gain insights into this property. HD5 bound natural glycoproteins > neoglycoproteins based on BSA > nonglycosylated B...
Cell-penetrating peptides (CPPs) are small cationic peptides that cross the cell membrane while carrying macromolecular cargoes. We use solid-state NMR to investigate the structure and lipid interaction of two cationic residues, Arg(10) and Lys(13), in the CPP penetratin. (13)C chemical shifts indicate that Arg(10) adopts a rigid beta-strand confor...
