Can Structural Differences between SARS-CoV and SARS-CoV-2 explain Differences in Drug Efficacy?

The severe acute respiratory syndrome corona virus (SARS-CoV)and severe acute respiratory syndrome corona virus-2 (SARS-CoV-2), both virus spike proteins are recognized by the cell surface receptors, human angiotensin converting enzyme-2 (ACE-2).These viruses gain access into the host cell through ACE-2receptors.The main aim of the current study was to elaborate on the structural differences in the receptor binding domain (RBD) of spike glycoprotein in SARS-CoV and SARS-CoV-2 that bind at the same active binding site. The crystal structures of receptor bound spikes of SARS-CoV and SARS-CoV-2 were compared using UCSF Chimera and pyMOL software which revealed significant differences in the receptor binding domain of the spikes with variation in the amino acid residues. It was also observed that conformational changes occurred in the amino acid residues at the binding site on ACE-2 receptor. These conformational changes in ACE-2 binding site of SARS-CoV-2 were attributed to a greater number of contacts forming between RBD and active binding site when compared to that of SARS-CoV and could explain any differences in the effectiveness of drugs against SARS-CoV and SARS-CoV-2. In addition, using Autodock vina software, drugs that were found to be effective in SARS-COV treatment were docked at active binding site on ACE-2.Antivirals, ACE-2 inhibitors and corticosteroids were docked at the active binding site domains of ACE-2 receptor in SARS-CoV andSARS-CoV-2.Antivirals such as Oseltamivir, Umifenovir, Favipiravir, Remdesivir and antibiotics such as Moxifloxacin and Azithromycin, Ace-2. Antivirals inhibitors such as Losartan and steroids such as Dexamethasone have shown a greater negative docking score (indicating more binding affinity) in and SARS-CoV-2 when compared to that of SARS-CoV. This kind of preliminary analysis using computational techniques could help in screening and repurposing the existing drugs that are potential in treating new diseases such as CoVID-19

A Rational Approach for Creating Peptides Mimicking Antibody Binding

This study reports a novel method to design peptides that mimic antibody binding. Using the Knob-Socket model for protein-protein interaction, the interaction surface between Cetuximab and EGFR was mapped. EGFR binding peptides were designed based on geometry and the probability of the mapped knob-sockets pairs. Designed peptides were synthesized and then characterized for binding specificity, affinity, cytotoxicity of drug-peptide conjugate and inhibition of phosphorylation. In cell culture studies, designed peptides specifically bind and internalize to EGFR overexpressing cells with three to four-fold higher uptake compared to control cells that do not overexpress EGFR. The designed peptide, Pep11, bound to EGFR with

Synthetic Antibody Mimic Peptides

The present disclosure relates to compositions and methods comprising peptide molecules that mimic the binding and functional properties of native antibodies relative to their respective targets. Some embodiments comprise peptide-drug conjugates (PDCs) comprising the mimic peptides disclosed herein. The targets of these mimic peptides include epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor (VEGF), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1). The present disclosure comprises application of the knob-socket computational model to design antibody mimics for proteins

Rational Design of Peptide Ligands Based on Knob−Socket Protein Packing Model Using CD13 as a Prototype Receptor

Structure-based computational peptide design methods have gained significant interest in recent years owing to the availability of structural insights into protein–protein interactions obtained from the crystal structures. The majority of these approaches design new peptide ligands by connecting the crucial amino acid residues from the protein interface and are generally not based on any predicted receptor–ligand interaction. In this work, a peptide design method based on the Knob–Socket model was used to identify the specific ligand residues packed into the receptor interface. This method enables peptide ligands to be designed rationally by predicting amino acid residues that will fit best at the binding site of the receptor protein. In this, specific peptide ligands were designed for the model receptor CD13, overexpression of which has been observed in several cancer types. From the initial library of designed peptides, three potential candidates were selected based on simulated energies in the CD13 binding site using the programs molecular operating environment and AutoDock Vina. In the CD13 enzymatic activity inhibition assay, the three identified peptides exhibited 2.7–7.4 times lower IC50 values (GYPAY, 227 μM; GFPAY, 463 μM; GYPAVYLF, 170 μM) as compared to the known peptide ligand CNGRC (C1–C5) (1260 μM). The apparent binding affinities of the peptides (GYPAY, Ki = 54.0 μM; GFPAY, Ki = 74.3 μM; GYPAVYLF, Ki = 38.8 μM) were 10–20 times higher than that of CNGRC (C1–C5) (Ki = 773 μM). The double reciprocal plots from the steady-state enzyme kinetic assays confirmed the binding of the peptides to the intended active site of CD13. The cell binding and confocal microscopy assays showed that the designed peptides selectively bind to the CD13 on the cell surface. Our study demonstrates the feasibility of a Knob–Socket-based rational design of novel peptide ligands in improving the identification of specific binding versus current more labor-intensive methods

BINGE EATING DISORDERS; UPDATED AND EMERGING APPROACHES

Objective: Binge eating disorders (BED) recently become a global health care issue for clinicians with detrimental effects on all organ systems. A multidisciplinary strategy including pharmacotherapy is required for its management. Methods: This review is intended to comparatively evaluate the relative efficacy of different pharmacological agents in BED treatment with new therapeutic approaches, focusing on the clinical evidence and on Phase III randomized controlled trials. Results: Data suggest that certain treatments have advantages over placebos to reduce binge eating features; however, the small duration of such research with the lack of adequately sized trials was the major limitation in interpreting these findings. Furthermore, these medications are mostly not greatly efficient for BED associated with obesity except for topiramate, which markedly improves the features of binge episodes with weight loss. Till now, lisdexamfetamine is still the only drug with regulatory permission for BED therapy; however, its weight loss efficacy has not been established. Conclusion: Drugs alone or in combination approaches may be useful pharmacotherapies to yield promising outcomes acutely and over longer-term follow-up in the treatment of BED

TRANSETHOSOMES AS BREAKTHROUGH TOOL FOR CONTROLLED TRANSDERMAL DELIVERY OF DEXKETOPROFEN TROMETAMOL: DESIGN, FABRICATION, STATISTICAL OPTIMIZATION, IN VITRO, AND EX VIVO CHARACTERIZATION

Objective: Transethosomes (TEs) have introduced an emerging avenue of interest in vesicular research for transdermal delivery of drugs and can be a proper delivery system for painkillers like NSAIDS. This study aimed to formulate and characterize the potential of TE to enhance the transdermal transport of Dexketoprofen trometamol (DKT) to achieve controlled pain management compared to DKT solution. Methods: Factorial design (23) was adopted to appraise the influence of independent variables, namely, Lipoid S100 and surfactant concentrations and surfactant type (X3) on the % solubilization efficiency (% SE), vesicle size (VS), and % release efficiency (% RE). Thin film hydration was the preferred approach for preparing TEs where vesicle size, zeta potential, polydispersity index, %SE and %RE were investigated. The optimized formula was nominated and subjected to several studies. For the permeation study, optimum TE was incorporated into carbapol gel base for comparison with DKT solution. Also, an accelerated stability study was assessed for optimized formula. Results: All the prepared DKT-loaded TEs revealed acceptable VS, PDI, and ZP. The highest %SE (86.08±1.05 %) and lowest %RE (44.62±1.36 %) were observed in case of F1. The optimized formula (F1) displayed VS of 133.2±1.62 nm, PDI of 0.342±0.03 and ZP of-21.6±2.45 mV. F1 revealed enhanced skin permeation of a 2.6-fold increase compared with DKT solution. Moreover, F1 was stable upon storage and a non-significant change (P>0.05) was observed. Conclusion: DKT was successfully incorporated into vesicle carrier and can signify an alternative option for providing this therapy, bypassing the poor bioavailability and considerable adverse consequences of using the oral route besides improved patient compliance

Phase I Clinical Trial of 5-Fluoro-Pyrimidinone (5FP), an Oral Prodrug of 5-Fluorouracil (5FU)

Purpose: 5-Fluoro-Pyrimidinone (5FP)is an oral pro-drug of 5-Fluorouracil(5FU), and is converted to 5FU by hepaticaldehyde oxidase. Preclinically, 5FPdemonstrated anti-tumor activity againstcolon 38 and P 388 leukemia models in mice. Using an accelerated titration trial designwith one patient cohorts and initial 100%escalations, a Phase I trial was conductedto determine the maximum tolerated dose(MTD) of 5FP and describe its toxicity andpharmacokinetic profile.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45222/1/10637_2004_Article_390715.pd

Characterization of polymorphic forms and in vitro release of etoposide from poly-DL-lactic and poly-DL-lactic-co-glycolic acid micromatrices

Etoposide has been shown to be effective in the treatment of testicular and small-cell lung cancers, lymphoma, leukemia and Kaposi\u27s sarcoma. Several clinical investigations have suggested that the prolonged maintenance of greater than 1 $\mu$g/ml concentration in plasma would provide better therapeutic response in patients. Thus use of a sustained/controlled release formulation of etoposide was indicated. This investigation focused on the potential for the development of a sustained/controlled release dosage form of etoposide for a 7-15 day delivery using selected polylactic and polylactic-co-glycolic acid polymers. During the course of studies involving the enhancement of aqueous solubility of etoposide in our laboratory evidence of a potential thermally induced polymorphic transition was detected. Therefore, further characterization of this phenomenon was also included in this investigation. Thermal behavior of etoposide was characterized by differential scanning calorimetry, thermal gravimetric analysis, X-ray diffractometry, mass spectroscopy, IR spectra and HPLC analyses. A method for the preparation of micromatrices of etoposide was developed utilizing a suspension and solvent evaporation technique. DSC, IR and NMR investigations did not indicate any potential etoposide-polymer interaction. Etoposide I, a monohydrate, underwent a dehydration reaction between 85-115\sp\circC to yield Etoposide Ia, which upon further heating melted at 198\sp\circC and crystallized to a new polymorph, Etoposide IIa at 206\sp\circC. Etoposide IIa was found to melt at 269\sp\circC and converted to its hydrated form, Etoposide II when exposed to atmosphere at room temperature. The polymorphic transition was found to be irreversible and monotropic. Etoposide I, the currently marketed drug was used in all delivery systems examined. Formulation studies with polylactic acid polymers indicated that the molecular weight of the polymer was a key parameter in influencing the percent of drug entrapped in the micromatrices, particles size distribution and the drug release profiles. Glycolide-containing polymers demonstrated control of etoposide release only at low drug loadings: larger micromatrices showing better control. Polylactic acid 50,000 at 1:5 and 1:15 drug to polymer ratios exhibited maximum rate of drug release of 1.57 mg/hr. At this release rate, a delivery system containing 350 mg of etoposide could be expected to maintain a plasma concentration of 1.08 $\mu$g/ml over a period of 7 days. Additionally, drug release profile of polylactide-co-glycolide (85:15, 75-180 $\mu$m) microsphere formulation with 1:10 drug to polymer ratio, was found to be more appropriate for a 15-day release system based upon 700 mg of etoposide

Characterization of polymorphic forms and in vitro release of etoposide from poly-DL-lactic and poly-DL-lactic-co-glycolic acid micromatrices

Etoposide has been shown to be effective in the treatment of testicular and small-cell lung cancers, lymphoma, leukemia and Kaposi\u27s sarcoma. Several clinical investigations have suggested that the prolonged maintenance of greater than 1 $\mu$g/ml concentration in plasma would provide better therapeutic response in patients. Thus use of a sustained/controlled release formulation of etoposide was indicated. This investigation focused on the potential for the development of a sustained/controlled release dosage form of etoposide for a 7-15 day delivery using selected polylactic and polylactic-co-glycolic acid polymers. During the course of studies involving the enhancement of aqueous solubility of etoposide in our laboratory evidence of a potential thermally induced polymorphic transition was detected. Therefore, further characterization of this phenomenon was also included in this investigation. Thermal behavior of etoposide was characterized by differential scanning calorimetry, thermal gravimetric analysis, X-ray diffractometry, mass spectroscopy, IR spectra and HPLC analyses. A method for the preparation of micromatrices of etoposide was developed utilizing a suspension and solvent evaporation technique. DSC, IR and NMR investigations did not indicate any potential etoposide-polymer interaction. Etoposide I, a monohydrate, underwent a dehydration reaction between 85-115\sp\circC to yield Etoposide Ia, which upon further heating melted at 198\sp\circC and crystallized to a new polymorph, Etoposide IIa at 206\sp\circC. Etoposide IIa was found to melt at 269\sp\circC and converted to its hydrated form, Etoposide II when exposed to atmosphere at room temperature. The polymorphic transition was found to be irreversible and monotropic. Etoposide I, the currently marketed drug was used in all delivery systems examined. Formulation studies with polylactic acid polymers indicated that the molecular weight of the polymer was a key parameter in influencing the percent of drug entrapped in the micromatrices, particles size distribution and the drug release profiles. Glycolide-containing polymers demonstrated control of etoposide release only at low drug loadings: larger micromatrices showing better control. Polylactic acid 50,000 at 1:5 and 1:15 drug to polymer ratios exhibited maximum rate of drug release of 1.57 mg/hr. At this release rate, a delivery system containing 350 mg of etoposide could be expected to maintain a plasma concentration of 1.08 $\mu$g/ml over a period of 7 days. Additionally, drug release profile of polylactide-co-glycolide (85:15, 75-180 $\mu$m) microsphere formulation with 1:10 drug to polymer ratio, was found to be more appropriate for a 15-day release system based upon 700 mg of etoposide

PREDICTIVE PHARMACOKINETIC MODEL BASED ON THE CORRELATION OF IN VITRO AND IN VIVO SUBLINGUAL ABSORPTION PARAMETERS

To develop a predictive pharmacokinetic model based on the correlation of in vitro and in vivo sublingual absorption parameters