Publications by authors named "Oded Ovadia"

The ongoing threat of COVID-19 has highlighted the need for effective prophylaxis and convenient therapies, especially for outpatient settings. We have previously developed highly potent single-domain (VHH) antibodies, also known as nanobodies, that target the Receptor Binding Domain (RBD) of the SARS-CoV-2 Spike protein and neutralize the Wuhan strain of the virus. In this study, we present a new generation of anti-RBD nanobodies with superior properties.

View Article and Find Full Text PDF

Painkillers are commonly used medications. Native peptide painkillers suffer from various pharmacological disadvantages, while small molecule painkillers like morphine are highly addictive. We present a general approach aimed to use backbone-cyclization to develop a peptidomimetic painkiller.

View Article and Find Full Text PDF

Recent structural studies on libraries of cyclic hexapeptides led to the identification of common backbone conformations that may be instrumental to the oral availability of peptides. Furthermore, the observation of differential Caco-2 permeabilities of enantiomeric pairs of some of these peptides strongly supports the concept of conformational specificity driven uptake and also suggests a pivotal role of carrier-mediated pathways for peptide transport, especially for scaffolds of polar nature. This work presents investigations on the Caco-2 and PAMPA permeability profiles of 13 selected N-methylated cyclic pentaalanine peptides derived from the basic cyclo(-D-Ala-Ala4 -) template.

View Article and Find Full Text PDF

Insufficient oral bioavailability is considered as a key limitation for the widespread development of peptides as therapeutics. While the oral bioavailability of small organic compounds is often estimated from simple rules, similar rules do not apply to peptides, and even the high oral bioavailability that is described for a small number of peptides is not well understood. Here we present two highly Caco-2 permeable template structures based on a library of 54 cyclo(-D-Ala-Ala(5)-) peptides with different N-methylation patterns.

View Article and Find Full Text PDF

Recent progress in peptide synthesis simplified the synthesis of multiple N-methylation of peptides. To evaluate how multiple N-methylation affects the bioavailability of peptides, a poly alanine cyclic hexapeptide library (n = 54), varying in the number of N-methyl (N-Me) groups (1-5 groups) and their position, was synthesized. The peptides were evaluated for their intestinal permeability in vitro using the Caco-2 model.

View Article and Find Full Text PDF

Importance Of The Field: Peptides are promising candidates as therapeutic agents due to their wide involvement in physiological processes. However, their often non-selective activity and their poor drug-like properties, mainly their inherent low stability to enzymatic degradation and poor oral bioavailability, limit their clinical potential. Somatostatin is a peptide hormone involved in many different biological functions.

View Article and Find Full Text PDF

A peptide-peptoid hybrid (peptomer) library was designed and synthesized, based on the sequence Phe-d-Phe-Arg-Trp-Gly. This sequence was previously found to specifically activate the melanocortin-4-receptor (MC4R) which participates in regulation of energy homeostasis and appetite. The library of peptomers included a peptoid bond in the Phe and/or d-Phe position and consisted of linear and backbone cyclic analogs, differed in their ring size.

View Article and Find Full Text PDF

Backbone cyclization (BC) and N-methylation have been shown to enhance the activity and/or selectivity of biologically active peptides and improve metabolic stability and intestinal permeability. In this study, we describe the synthesis, structure-activity relationship (SAR) and intestinal metabolic stability of a backbone cyclic peptide library, BL3020, based on the linear alpha-Melanocyte stimulating hormone analog Phe-D-Phe-Arg-Trp-Gly. The drug lead, BL3020-1, selected from the BL3020 library (compound 1) has been shown to inhibit weight gain in mice following oral administration.

View Article and Find Full Text PDF

Objective: Metformin is a polar positively charged compound. The aim of the study was to characterize its permeability across the human placenta using the ex vivo placental perfusion model.

Methods: Selected cotyledons from term placentas were cannulated and dually perfused.

View Article and Find Full Text PDF

The tetrapeptide sequence His-Phe-Arg-Trp, derived from melanocyte-stimulating hormone (alphaMSH) and its analogs, causes a decrease in food intake and elevates energy utilization upon binding to the melanocortin-4 receptor (MC4R). To utilize this sequence as an effective agent for treating obesity, we improved its metabolic stability and intestinal permeability by synthesizing a library of backbone cyclic peptidomimetic derivatives. One analog, peptide 1 (BL3020-1), was selected according to its selectivity in activating the MC4R, its favorable transcellular penetration through enterocytes and its enhanced intestinal metabolic stability.

View Article and Find Full Text PDF

A library of 18 hexapeptide analogs was synthesized, including sub-libraries of N- or C-methylation of the parent hexapeptide Phe-Gly-Gly-Gly-Gly-Phe, as well as backbone cyclized analogs of each linear analog with various ring sizes. N- or C-methylation as well as cyclization (but not backbone cyclization) have been suggested to improve intestinal permeability and metabolic stability of peptides in general. Here we aimed to assess their applicability to hydrophilic peptides.

View Article and Find Full Text PDF

An unselective cyclic peptide integrin ligand was sequentially N-methylated by a designed approach, where only the externally oriented (solvent exposed) amide bonds were N-methylated. The N-methylation resulted in tremendous enhancement in selectivity among the different integrin receptor subtypes (alpha5beta1, alphavbeta3, and alphaIIbbeta3). Conformational and docking studies were performed, which suggested that the receptor selectivity is principally caused by reduced backbone flexibility due to N-methylation.

View Article and Find Full Text PDF

Prokineticins (PKs), multifunctional secreted proteins, activate two endogenous G protein-coupled receptors (R) termed PK-R1 and PK-R2. It was suggested that PK1 acts selectively on the endothelium of endocrine glands, yet PK-Rs were also found in endothelial cells (EC) derived from other tissues. Therefore we examined here the characteristics of PK - system in EC derived from different vascular beds.

View Article and Find Full Text PDF

A highly vascular endocrine gland, the corpus luteum (CL) is an excellent model for the study of angiogenic factors. Prokineticins (PK-1 and -2), also termed endocrine-gland-derived vascular endothelial growth factor (VEGF) and BV8 are newly identified proteins described as selective angiogenic mitogens. We previously identified PK binding sites, two closely homologous G protein-coupled receptors (PK-R1 and PK-R2) in human and bovine ovarian cells, but their function remained unknown.

View Article and Find Full Text PDF

A PHP Error was encountered

Severity: Notice

Message: fwrite(): Write of 34 bytes failed with errno=28 No space left on device

Filename: drivers/Session_files_driver.php

Line Number: 272

Backtrace:

A PHP Error was encountered

Severity: Warning

Message: session_write_close(): Failed to write session data using user defined save handler. (session.save_path: /var/lib/php/sessions)

Filename: Unknown

Line Number: 0

Backtrace: