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Publications (47)
Introduction
The field of cancer therapy has undergone a major transformation in less than a decade due to the introduction of checkpoint inhibitors, the advent of next generation sequencing and the discovery of neoantigens. The key observation that the breadth of each patient’s immune response to the unique mutations or neoantigens present in thei...
The first example of a kinetic labeling library designed to enable the discovery of affinity labels is presented. Each library component (1) consists of a variable peptidyl component linked to a biotinyl moiety by a 4-mercaptobenzoyl linker in thioester format. We demonstrate that an affinity label can be uncovered by measuring reaction rates betwe...
PC-1505 is a C34 peptide derived from the heptad repeat 2 region of HIV-1 gp41 conjugated to human serum albumin for sustained
in vivo activity. One single preexposure dose of PC-1505 reduced viral RNA in HIV-1-infected SCID-hu Thy/Liv mice by 3.3 log10 and protected T cells from virus-mediated depletion. In contrast, a single preexposure dose of T...
HIV entry occurs by concerted conformational changes in the envelope protein complex on the surface of the virus. This complex is made up of a trimer of heterodimers of two subunits: surface subunit, gp120, and transmembrane subunit, gp41. Conformational changes in the envelope complex allow gp41 to mediate membrane fusion leading to exposure of tw...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Entry inhibitors of human immunodeficiency virus, type 1 (HIV-1) have been the focus of much recent research. C34, a potent fusion inhibitor derived from the HR2 region of gp41, was engineered into a 1:1 human serum albumin conjugate through stable covalent attachment of a maleimido-C34 analog onto cysteine 34 of albumin. This bioconjugate, PC-1505...
Prostate specific antigen (PSA) and human glandular kallikrein 2 (hK2), produced essentially by the prostate gland, are 237-amino acid monomeric proteins, with 79% identity in primary structure. Twenty-five anti-PSA monoclonal antibodies (Mabs) were studied for binding to a large array of synthetic linear peptides selected from computer models of P...
Peptide inhibitors corresponding to sequences in the six helix bundle structure of the fusogenic portion (gp41) of the HIV envelope glycoprotein have been successfully implemented in preventing HIV entry. These peptides bind to regions in HIV gp41 transiently exposed during the fusion reaction. In an effort to improve upon these entry inhibitors, w...
In vivo bioconjugation to the free thiol on Cys34 of serum albumin by a strategically placed reactive group on a bioactive peptide is a useful tool to extend plasma half-life. Three maleimido derivates of human GH-releasing factor (hGRF)(1-29) were synthesized and bioconjugated to human serum albumin ex vivo. All three human serum albumin conjugate...
A series of human insulin maleimido derivatives with short and long linkers was synthesized by exploiting the variations in the pK(a) values and environment of the three amino groups present in the protein. The syntheses were accomplished in organic solvent because of maleimide's instability in basic aqueous media. The derivatives thus obtained wer...
A series of analogs of GLP-1(7-36) amide containing a Nepsilon-(2-[2-[2-(3-maleimidopropylamido)ethoxy]ethoxy]acetyl)lysine has been synthesized and the resulting derivatives were bioconjugated to Cys34 of human serum albumin (HSA). The GLP-1-HSA bioconjugates were analyzed in vitro to assess the stabilizing effect of bioconjugation in the presence...
Three peptide fragments of the kringle 5 region of plasminogen and their respective N- and C-terminus maleimido derivatives conjugated to Cys34 of human serum albumin were evaluated in vitro using a human umbilical vein endothelial cell (HUVEC) migration assay and a human plasma stability assay. The N-terminus maleimido derivative of the 64 to 74 s...
Atrial natriuretic peptide (ANP) is a clinically useful anti-hypertensive hormone. Maleimide derivatives of ANP have been synthesized and conjugated to cysteine-34 of human serum albumin. The conjugates were analyzed to assess their stability, receptor binding affinity and ability to stimulate guanylyl-cyclase activity in rat lung fibroblasts.
The rapid degradation of native glucagon-like peptide 1 (GLP-1) by dipeptidyl peptidase-IV (DPP-IV) has fostered new approaches for generation of degradation-resistant GLP-1 analogues. We examined the biological activity of CJC-1131, a DPP-IV-resistant drug affinity complex (DAC) GLP-1 compound that conjugates to albumin in vivo. The CJC-1131 album...
A site-specific 1:1 dynorphin A-(1-13)-NH(2) derivative conjugated specifically to Cys 34 on human serum albumin (CCI-1035) was shown to be an opioid receptor agonist in vitro and to be a long lasting antinociceptive agent when administered intravenously to mice as assessed by an acetic acid writhing assay. When 10 micromol/kg of CCI-1035 was admin...
Red blood cells have been labeled with an anti-renin pharmacophore using the activated labeling agent Boc-Phe-His-ACHPA-Ile-6-NH(CH2)5CO-NHS (4) and the corresponding sulfo-NHS-ester (5). Renin inhibition by labeled cells varies according to the concentrations of 4 or 5 used in the labeling protocols, and with the densities of the red cells employe...
HIV-1 peptides having at least one point mutation between position 593 and 611 of the HIV-1 gp160 amino acid sequence. The point mutation either is at position 604 or 610, or both positions. Immunoassays which utilize these peptides are provided, as well as, diagnostic test kits which contain these peptides.
The a determinant of hepatitis B surface antigen (HBsAg) is the most critical determinant for both diagnosis and immunoprophylaxis of the hepatitis B virus. We have used synthetic peptides and an anti-a mAb to identify a peptide sequence corresponding to amino acid residues 117 to 128 of HBsAg as an antigenic epitope contributing to the a determina...
Prostate-specific antigen (PSA), the most useful tumor marker for prostate cancer, is one of three members of the human kallikrein family of serine proteases. PSA and human glandular kallikrein (hK2, previously called hGK-1) share extensive homology and are both produced in the prostate under androgen control. Our goals were to use molecular modeli...
The thiohydroxamic acid ester (I) derived from pyridine-2-thione (III) is sonicated in tetrachloromethane in the presence of thiophenol (II) to undergo radical-induced decarboxylation, yielding the thione (III), the hydrocarbon (IV), and diphenyl disulfide (V).
The carboxylic acids (I) are converted to the acid chlorides and then coupled with the N-hydroxythiopyridone (II) to produce the N-acyloxy derivatives (III).
Carbon centered radicals obtained by decarboxylative transformation of suitable thiohydroxamate esters react with group Va trisphenyl-sulphides to give intermediates of general formula R-M(SPh)2 (M = As, Sb, Bi). These react spontaneously with air to give the corresponding alcohols. This procedure is especially useful in the case where M=Sb. It is...
The thiohydroxamic esters (I) are irradiated in the presence of the halotrichloromethanes (II) to give the halides (III), together with the pyridyl thioethers (IV) and carbon dioxide (V).
The generality of light initiated halogenative decarboxylation of thiohydroxamic esters was studied. This method gave high yields of alkyl chlorides, bromides and iodides derived from primary, secondary and tertiairy substituted carboxylic acids.
The reaction of a wide range of thiohydroxamate esters such as (I) with the tris(phenylsulfide) (II) is studied.
Irradiation of esters derived from aliphatic or alicyclic carboxylic acids and N-hydroxy-2-thiopyridone in the presence of various quinones gives high yields of the corresponding adducts (e.g. ) with net loss of carbon dioxide.
Esters (mixed anhydrides) derived from aliphatic or alicyclic carboxylic acids (RCO2H) and thiohydroxamic acids or undergo a thermally or photochemically induced radical chain reaction to give sulphides with loss of carbon dioxide. On irradiation at low-temperature however, the chain reaction is essentially supressed. Under these conditions moderat...
The symmetrical dichalcogenides (I), (IV), and (VII) are thermally or photochemically cleaved in the presence of the N-acyloxyheterocycles (II) and (V) to produce the chalcogenides (III), (VI), and (VIII).
The thiohydroxamic acid (II) is converted to the mixed anhydrides (III).
The mixed anhydrides (Ib) and (IIb) are prepared from the acid chlorides of the bisnorcholic acid derivative (Ia) or the hederagenin derivative (IIa).
Irradiation with a tungsten lamp of mixed anhydrides (e.g. 8) derived from aliphatic or alicyclic carboxylic acids and N-hydroxy-2-pyridine thione 3 in the presence of a disulphide, diselenide or ditelluride gives the corresponding chalcogenide (e.g. 9, 10, or 11) in high yield. The process involves a radical decarboxylation followed by SH2 reactio...
Esters (mixed anhydrides) derived from aliphatic or alicyclic carboxylic acids (RCO2H) and thiohydroxamic acids or undergo a thermally or photochemically induced radical chain reaction to give sulphides with loss of carbon dioxide. On irradiation at low-temperature however, the chain reaction is essentially supressed. Under these conditions moderat...
L-Selenomethionine and L-selenocystine were prepared in high overall yields from protected L-glutamic and L-aospartic acid derivatives respectively. Irradiation of the mixed anhydrides (esters) derived from (e.g. ) in the presence of dimethyldiselenide provided the protected L-selenomethionine directly. We have shown that triselenocyanide Se3(CN)2...
Thiohydroxomic corboxylic mixed anhydrides (e.g. ) react at room temperature with (PhS)3P to give, through a decarboxylative phosphorylation reaction, the corresponding dithiophosphonates in moderate yields.
Das gemischte Anhydrid (I) wird durch die Antimonverbindung (II) in Gegenwart von Sauerstoff und Wasser über verschiedene Zwischenstufen zum Alkohol (III) gespalten, dabei entstehen außerdem die Verbindungen (IV)-(VII).
Aus der cyclischen Thiohydroxamsäure (I) erhält man mit dem Säurechlorid (II) das Acylierungsprodukt (III), das beim Erhitzen mit Diphenyldisulfid unter COg-Abspaltung in das Phenylsulfid (IV) übergeführt wird.
Esters (mixed anhydrides) of carboxylic acids and thiohydroxamic acid (2) react with tris(phenylthio)antimony in the presence of oxygen and water to give high yields of nor-alcohols.
Thiohydroxamic-carboxylic mixed anhydrides can be decarboxylated in the presence of diaryl disulphides, diselenides and ditellurides to give sulphides, selenides and tellurides respectively in reasonable to good yield.
Esters (mixed anhydrides) derived from aliphatic or alicyclic carboxylic acids (RCO2H) and thiohydroxamic acids or undergo a thermally or photochemically induced radical chain reaction to give sulphides with loss of carbon dioxide. On irradiation at low-temperature however, the chain reaction is essentially supressed. Under these conditions moderat...
