scholarly journals PPI Modulators of E6 as Potential Targeted Therapeutics for Cervical Cancer: Progress and Challenges in Targeting E6

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 3004
Author(s):  
Lennox Chitsike ◽  
Penelope J. Duerksen-Hughes
Keyword(s):  
Cervical Cancer ◽  
Protein Interactions ◽  
Current Knowledge ◽  
Human Subjects ◽  
Protein Protein Interactions ◽  
Cellular Targets ◽  
E6 Oncoprotein ◽  
Cytotoxic Therapies ◽  
Small Molecule Modulators ◽  
Published Research

Advanced cervical cancer is primarily managed using cytotoxic therapies, despite evidence of limited efficacy and known toxicity. There is a current lack of alternative therapeutics to treat the disease more effectively. As such, there have been more research endeavors to develop targeted therapies directed at oncogenic host cellular targets over the past 4 decades, but thus far, only marginal gains in survival have been realized. The E6 oncoprotein, a protein of human papillomavirus origin that functionally inactivates various cellular antitumor proteins through protein–protein interactions (PPIs), represents an alternative target and intriguing opportunity to identify novel and potentially effective therapies to treat cervical cancer. Published research has reported a number of peptide and small-molecule modulators targeting the PPIs of E6 in various cell-based models. However, the reported compounds have rarely been well characterized in animal or human subjects. This indicates that while notable progress has been made in targeting E6, more extensive research is needed to accelerate the optimization of leads. In this review, we summarize the current knowledge and understanding of specific E6 PPI inhibition, the progress and challenges being faced, and potential approaches that can be utilized to identify novel and potent PPI inhibitors for cervical cancer treatment.

Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

2018 ◽  
Vol 25 (1) ◽  
pp. 5-21 ◽  
Author(s):  
Ylenia Cau ◽  
Daniela Valensin ◽  
Mattia Mori ◽  
Sara Draghi ◽  
Maurizio Botta
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Specific Protein ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Protein Partners ◽  
High Sequence Homology ◽  
Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

Polyamines: Naturally occurring small molecule modulators of electrostatic protein–protein interactions

2010 ◽  
Vol 104 (2) ◽  
pp. 118-125 ◽  
Author(s):  
Anja Berwanger ◽  
Susanne Eyrisch ◽  
Inge Schuster ◽  
Volkhard Helms ◽  
Rita Bernhardt
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Naturally Occurring ◽  
Small Molecule Modulators

scholarly journals Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 106
Author(s):  
Pavel V. Ershov ◽  
Yuri V. Mezentsev ◽  
Alexis S. Ivanov
Keyword(s):  
Protein Interactions ◽  
Targeted Delivery ◽  
Protein Complexes ◽  
Protein Protein Interactions ◽  
Good Efficiency ◽  
Cellular Targets ◽  
Proteolytic Stability ◽  
Clinically Significant

The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area (interfaces) of the vast majority of PPIs has some features, such as geometrical and biochemical complementarities, “hot spots”, as well as an extremely low mutation rate that give us key knowledge to influence these PPIs. Exogenous regulation of PPIs is aimed at both inhibiting the assembly and/or destabilization of protein complexes. Often, the design of such modulators is associated with some specific problems in targeted delivery, cell penetration and proteolytic stability, as well as selective binding to cellular targets. Recent progress in interfacial peptide design has been achieved in solving all these difficulties and has provided a good efficiency in preclinical models (in vitro and in vivo). The most promising peptide-containing therapeutic formulations are under investigation in clinical trials. In this review, we update the current state-of-the-art in the field of interfacial peptides as potent modulators of a number of disease-related PPIs. Over the past years, the scientific interest has been focused on following clinically significant heterodimeric PPIs MDM2/p53, PD-1/PD-L1, HIF/HIF, NRF2/KEAP1, RbAp48/MTA1, HSP90/CDC37, BIRC5/CRM1, BIRC5/XIAP, YAP/TAZ–TEAD, TWEAK/FN14, Bcl-2/Bax, YY1/AKT, CD40/CD40L and MINT2/APP.

Small Molecule Modulators of Protein–Protein Interactions: Selected Case Studies

2014 ◽  
Vol 114 (9) ◽  
pp. 4640-4694 ◽  
Author(s):  
Madhu Aeluri ◽  
Srinivas Chamakuri ◽  
Bhanudas Dasari ◽  
Shiva Krishna Reddy Guduru ◽  
Ravikumar Jimmidi ◽  
...  
Keyword(s):  
Case Studies ◽  
Small Molecule ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Small Molecule Modulators

scholarly journals A Dual Luciferase Multiplexed High-Throughput Screening Platform for Protein-Protein Interactions

2003 ◽  
Vol 8 (6) ◽  
pp. 676-684 ◽  
Author(s):  
Bart W. Nieuwenhuijsen ◽  
Youping Huang ◽  
Yuren Wang ◽  
Fernando Ramirez ◽  
Gary Kalgaonkar ◽  
...  
Keyword(s):  
Reporter Gene ◽  
Small Molecule ◽  
High Throughput ◽  
Protein Interactions ◽  
Renilla Luciferase ◽  
Luciferase Reporter ◽  
Rgs Proteins ◽  
Protein Protein Interactions ◽  
Luciferase Reporter Gene ◽  
Small Molecule Modulators

To study the biology of regulators of G-protein signaling (RGS) proteins and to facilitate the identification of small molecule modulators of RGS proteins, the authors recently developed an advanced yeast 2-hybrid (YTH) assay format for GαZand RGS-Z1. Moreover, they describe the development of a multiplexed luciferase-based assay that has been successfully adapted to screen large numbers of small molecule modulators of protein-protein interactions. They generated and evaluated 2 different luciferase reporter gene systems for YTH interactions, a Gal4 responsive firefly luciferase reporter gene and a Gal4 responsive Renilla luciferase reporter gene. Both the firefly and Renilla luciferase reporter genes demonstrated a 40-to 50-fold increase in luminescence in strains expressing interacting YTH fusion proteins versus negative control strains. Because the firefly and Renilla luciferase proteins have different substrate specificity, the assays were multiplexed. The multiplexed luciferase-based YTH platform adds speed, sensitivity, simplicity, quantification, and efficiency to YTH high-throughput applications and therefore greatly facilitates the identification of small molecule modulators of protein-protein interactions as tools or potential leads for drug discovery efforts.

scholarly journals Activities and regulation of peptidoglycan synthases

2015 ◽  
Vol 370 (1679) ◽  
pp. 20150031 ◽  
Author(s):  
Alexander J. F. Egan ◽  
Jacob Biboy ◽  
Inge van't Veer ◽  
Eefjan Breukink ◽  
Waldemar Vollmer
Keyword(s):  
Escherichia Coli ◽  
Protein Interactions ◽  
Cytoplasmic Membrane ◽  
Current Knowledge ◽  
Protein Protein Interactions ◽  
Penicillin Binding Proteins ◽  
Multiple Protein ◽  
Cell Division Protein ◽  
The Impact

Peptidoglycan (PG) is an essential component in the cell wall of nearly all bacteria, forming a continuous, mesh-like structure, called the sacculus, around the cytoplasmic membrane to protect the cell from bursting by its turgor. Although PG synthases, the penicillin-binding proteins (PBPs), have been studied for 70 years, useful in vitro assays for measuring their activities were established only recently, and these provided the first insights into the regulation of these enzymes. Here, we review the current knowledge on the glycosyltransferase and transpeptidase activities of PG synthases. We provide new data showing that the bifunctional PBP1A and PBP1B from Escherichia coli are active upon reconstitution into the membrane environment of proteoliposomes, and that these enzymes also exhibit DD-carboxypeptidase activity in certain conditions. Both novel features are relevant for their functioning within the cell. We also review recent data on the impact of protein–protein interactions and other factors on the activities of PBPs. As an example, we demonstrate a synergistic effect of multiple protein–protein interactions on the glycosyltransferase activity of PBP1B, by its cognate lipoprotein activator LpoB and the essential cell division protein FtsN.

Biophysical and computational fragment-based approaches to targeting protein–protein interactions: applications in structure-guided drug discovery

2012 ◽  
Vol 45 (4) ◽  
pp. 383-426 ◽  
Author(s):  
Anja Winter ◽  
Alicia P. Higueruelo ◽  
May Marsh ◽  
Anna Sigurdardottir ◽  
Will R Pitt ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Interactions ◽  
Active Sites ◽  
Current Knowledge ◽  
Chemical Space ◽  
Isothermal Calorimetry ◽  
Protein Protein Interactions ◽  
Regulatory Pathways ◽  
Drug Candidates ◽  
X Ray Crystallography

AbstractDrug discovery has classically targeted the active sites of enzymes or ligand-binding sites of receptors and ion channels. In an attempt to improve selectivity of drug candidates, modulation of protein–protein interfaces (PPIs) of multiprotein complexes that mediate conformation or colocation of components of cell-regulatory pathways has become a focus of interest. However, PPIs in multiprotein systems continue to pose significant challenges, as they are generally large, flat and poor in distinguishing features, making the design of small molecule antagonists a difficult task. Nevertheless, encouragement has come from the recognition that a few amino acids – so-called hotspots – may contribute the majority of interaction-free energy. The challenges posed by protein–protein interactions have led to a wellspring of creative approaches, including proteomimetics, stapled α-helical peptides and a plethora of antibody inspired molecular designs. Here, we review a more generic approach: fragment-based drug discovery. Fragments allow novel areas of chemical space to be explored more efficiently, but the initial hits have low affinity. This means that they will not normally disrupt PPIs, unless they are tethered, an approach that has been pioneered by Wells and co-workers. An alternative fragment-based approach is to stabilise the uncomplexed components of the multiprotein system in solution and employ conventional fragment-based screening. Here, we describe the current knowledge of the structures and properties of protein–protein interactions and the small molecules that can modulate them. We then describe the use of sensitive biophysical methods – nuclear magnetic resonance, X-ray crystallography, surface plasmon resonance, differential scanning fluorimetry or isothermal calorimetry – to screen and validate fragment binding. Fragment hits can subsequently be evolved into larger molecules with higher affinity and potency. These may provide new leads for drug candidates that target protein–protein interactions and have therapeutic value.

Evolutionary selection for protein aggregation

2012 ◽  
Vol 40 (5) ◽  
pp. 1032-1037 ◽  
Author(s):  
Natalia Sanchez de Groot ◽  
Marc Torrent ◽  
Anna Villar-Piqué ◽  
Benjamin Lang ◽  
Salvador Ventura ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Interactions ◽  
Current Knowledge ◽  
Protein Aggregates ◽  
Cellular Systems ◽  
Aggregation Process ◽  
Loss Of Function ◽  
Protein Protein Interactions ◽  
Wide Range ◽  
Range Of Functions

Protein aggregation is being found to be associated with an increasing number of human diseases. Aggregation can lead to a loss of function (lack of active protein) or to a toxic gain of function (cytotoxicity associated with protein aggregates). Although potentially harmful, protein sequences predisposed to aggregation seem to be ubiquitous in all kingdoms of life, which suggests an evolutionary advantage to having such segments in polypeptide sequences. In fact, aggregation-prone segments are essential for protein folding and for mediating certain protein–protein interactions. Moreover, cells use protein aggregates for a wide range of functions. Against this background, life has adapted to tolerate the presence of potentially dangerous aggregation-prone sequences by constraining and counteracting the aggregation process. In the present review, we summarize the current knowledge of the advantages associated with aggregation-prone stretches in proteomes and the strategies that cellular systems have developed to control the aggregation process.

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