The discovery and development of transthyretin amyloidogenesis inhibitors: what are the lessons?

2021 ◽  
Author(s):  
Bin Zhong ◽  
Xianhua Huang ◽  
Yizhou Zheng ◽  
Xiaohua Guo ◽  
Longhuo Wu
Keyword(s):  
Crown Ethers ◽  
Binding Sites ◽  
Amyloid Fibrils ◽  
Review Article ◽  
Therapeutic Management ◽  
Binding Modes ◽  
Therapeutic Approaches ◽  
Amyloid Diseases

Transthyretin (TTR) is associated with several human amyloid diseases. Various kinetic stabilizers have been developed to inhibit the dissociation of TTR tetramer and the formation of amyloid fibrils. Most of them are bisaryl derivatives, natural flavonoids, crown ethers and carborans. In this review article we focus on TTR tetramer stabilizers, genetic therapeutic approaches and fibril remodelers. The binding modes of typical bisaryl derivatives, natural flavonoids, crown ethers and carborans are discussed. Based on knowledge of the binding of thyroxine to TTR tetramer, many stabilizers have been screened to dock into the thyroxine binding sites, leading to TTR tetramer stabilization. Particularly, those stabilizers with unique binding profiles have shown great potential in developing the therapeutic management of TTR amyloidogenesis.

Reversibly Sampling Conformations and Binding Modes Using Molecular Darting

2020 ◽  
Author(s):  
Samuel C. Gill ◽  
David Mobley
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Sites ◽  
Degrees Of Freedom ◽  
Dynamics Simulation ◽  
Hiv Integrase ◽  
Binding Modes ◽  
System A ◽  
Multiple Binding ◽  
Internal Degrees Of Freedom

<div>Sampling multiple binding modes of a ligand in a single molecular dynamics simulation is difficult. A given ligand may have many internal degrees of freedom, along with many different ways it might orient itself a binding site or across several binding sites, all of which might be separated by large energy barriers. We have developed a novel Monte Carlo move called Molecular Darting (MolDarting) to reversibly sample between predefined binding modes of a ligand. Here, we couple this with nonequilibrium candidate Monte Carlo (NCMC) to improve acceptance of moves.</div><div>We apply this technique to a simple dipeptide system, a ligand binding to T4 Lysozyme L99A, and ligand binding to HIV integrase in order to test this new method. We observe significant increases in acceptance compared to uniformly sampling the internal, and rotational/translational degrees of freedom in these systems.</div>

Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

2020 ◽  
Vol 20 (11) ◽  
pp. 1017-1030
Author(s):  
Haonan Zhang ◽  
Zhengquan Gao ◽  
Chunxiao Meng ◽  
Xiangqian Li ◽  
Dayong Shi
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Binding Sites ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Cancer Drug ◽  
Cellular Activity ◽  
Binding Modes ◽  
Inhibitor Binding ◽  
Protein Tyrosine

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.

scholarly journals Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607

2021 ◽  
Vol 141 (5) ◽  
pp. 697-708
Author(s):  
Yang Shi ◽  
Alexey G. Murzin ◽  
Benjamin Falcon ◽  
Alexander Epstein ◽  
Jonathan Machin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Binding Sites ◽  
Binding Activity ◽  
Cortical Atrophy ◽  
Binding Modes ◽  
Major Site ◽  
Age Related ◽  
Positron Emission

AbstractTau and Aβ assemblies of Alzheimer’s disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.

scholarly journals Current status of therapeutic approaches and vaccines for SARS-CoV-2

2021 ◽  
Author(s):  
Braira Wahid ◽  
Anam Amir ◽  
Ayesha Ameen ◽  
Muhammad Idrees
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Review Article ◽  
Experimental Designs ◽  
Current Status ◽  
Therapeutic Approaches ◽  
Efficacious Treatment ◽  
Rapid Pace ◽  
Global Health Challenge

SARS-CoV-2, declared a pandemic in March 2020, is the current global health challenge. The global bioburden of this virus is increasing at a rapid pace. Many antiviral drugs and vaccines have been registered for clinical trials because of their inhibitory activity observed in vitro. Currently, five types of vaccines have successfully passed Phase IV clinical trial and are being administered in populations worldwide. A plethora of experimental designs have been proposed worldwide in order to find a safe and efficacious treatment option. Therefore, it is necessary to provide baseline data and information to clinicians and researchers so that they can review the current status of therapeutics and efficacy of already developed vaccines. This review article summarizes all therapeutic options that may help to combat SARS-CoV-2.

scholarly journals α-Lactalbumin, Amazing Calcium-Binding Protein

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1210
Author(s):  
Eugene A. Permyakov
Keyword(s):  
Oleic Acid ◽  
Metal Ions ◽  
Metal Binding ◽  
Binding Sites ◽  
Calcium Binding ◽  
Amyloid Fibrils ◽  
Binding Protein ◽  
Molten Globule ◽  
Bacterial Cells ◽  
Practical Applications

α-Lactalbumin (α-LA) is a small (Mr 14,200), acidic (pI 4–5), Ca2+-binding protein. α-LA is a regulatory component of lactose synthase enzyme system functioning in the lactating mammary gland. The protein possesses a single strong Ca2+-binding site, which can also bind Mg2+, Mn2+, Na+, K+, and some other metal cations. It contains several distinct Zn2+-binding sites. Physical properties of α-LA strongly depend on the occupation of its metal binding sites by metal ions. In the absence of bound metal ions, α-LA is in the molten globule-like state. The binding of metal ions, and especially of Ca2+, increases stability of α-LA against the action of heat, various denaturing agents and proteases, while the binding of Zn2+ to the Ca2+-loaded protein decreases its stability and causes its aggregation. At pH 2, the protein is in the classical molten globule state. α-LA can associate with membranes at neutral or slightly acidic pH at physiological temperatures. Depending on external conditions, α-LA can form amyloid fibrils, amorphous aggregates, nanoparticles, and nanotubes. Some of these aggregated states of α-LA can be used in practical applications such as drug delivery to tissues and organs. α-LA and some of its fragments possess bactericidal and antiviral activities. Complexes of partially unfolded α-LA with oleic acid are cytotoxic to various tumor and bacterial cells. α-LA in the cytotoxic complexes plays a role of a delivery carrier of cytotoxic fatty acid molecules into tumor and bacterial cells across the cell membrane. Perhaps in the future the complexes of α-LA with oleic acid will be used for development of new anti-cancer drugs.

scholarly journals A network of phosphatidylinositol 4,5-bisphosphate binding sites regulates gating of the Ca2+-activated Cl− channel ANO1 (TMEM16A)

2019 ◽  
Vol 116 (40) ◽  
pp. 19952-19962 ◽  
Author(s):  
Kuai Yu ◽  
Tao Jiang ◽  
YuanYuan Cui ◽  
Emad Tajkhorshid ◽  
H. Criss Hartzell
Keyword(s):  
Protein Interactions ◽  
Binding Sites ◽  
Neuronal Excitability ◽  
Computational Study ◽  
Channel Gating ◽  
Md Simulations ◽  
Fluid Secretion ◽  
Hydroxyl Groups ◽  
Binding Modes ◽  
Cytoplasmic Extension

ANO1 (TMEM16A) is a Ca2+-activated Cl− channel that regulates diverse cellular functions including fluid secretion, neuronal excitability, and smooth muscle contraction. ANO1 is activated by elevation of cytosolic Ca2+ and modulated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Here, we describe a closely concerted experimental and computational study, including electrophysiology, mutagenesis, functional assays, and extended sampling of lipid–protein interactions with molecular dynamics (MD) to characterize PI(4,5)P2 binding modes and sites on ANO1. ANO1 currents in excised inside-out patches activated by 270 nM Ca2+ at +100 mV are increased by exogenous PI(4,5)P2 with an EC50 = 1.24 µM. The effect of PI(4,5)P2 is dependent on membrane voltage and Ca2+ and is explained by a stabilization of the ANO1 Ca2+-bound open state. Unbiased atomistic MD simulations with 1.4 mol% PI(4,5)P2 in a phosphatidylcholine bilayer identified 8 binding sites with significant probability of binding PI(4,5)P2. Three of these sites captured 85% of all ANO1–PI(4,5)P2 interactions. Mutagenesis of basic amino acids near the membrane–cytosol interface found 3 regions of ANO1 critical for PI(4,5)P2 regulation that correspond to the same 3 sites identified by MD. PI(4,5)P2 is stabilized by hydrogen bonding between amino acid side chains and phosphate/hydroxyl groups on PI(4,5)P2. Binding of PI(4,5)P2 alters the position of the cytoplasmic extension of TM6, which plays a crucial role in ANO1 channel gating, and increases the accessibility of the inner vestibule to Cl− ions. We propose a model consisting of a network of 3 PI(4,5)P2 binding sites at the cytoplasmic face of the membrane allosterically regulating ANO1 channel gating.

scholarly journals Targeting the Gut Microbiota in Chagas Disease: What Do We Know so Far?

2020 ◽  
Vol 11 ◽  
Author(s):  
Eduardo Duarte-Silva ◽  
Livia H. Morais ◽  
Gerard Clarke ◽  
Wilson Savino ◽  
Christina Peixoto
Keyword(s):  
Immune Response ◽  
Gut Microbiota ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Current Data ◽  
Review Article ◽  
Microbiota Composition ◽  
Comorbid Conditions ◽  
Therapeutic Approaches ◽  
Gut Microbiota Composition

Chagas disease (CD) is a tropical and still neglected disease caused by Trypanosoma cruzi that affects &gt;8 million of people worldwide. Although limited, emerging data suggest that gut microbiota dysfunction may be a new mechanism underlying CD pathogenesis. T. cruzi infection leads to changes in the gut microbiota composition of vector insects, mice, and humans. Alterations in insect and mice microbiota due to T. cruzi have been associated with a decreased immune response against the parasite, influencing the establishment and progression of infection. Further, changes in the gut microbiota are linked with inflammatory and neuropsychiatric disorders, comorbid conditions in CD. Therefore, this review article critically analyses the current data on CD and the gut microbiota of insects, mice, and humans and discusses its importance for CD pathogenesis. An enhanced understanding of host microbiota will be critical for the development of alternative therapeutic approaches to target CD, such as gut microbiota-directed interventions.

scholarly journals Molecular Modeling Studies on the Interactions of Aflatoxin B1 and Its Metabolites with Human Acetylcholinesterase. Part II: Interactions with the Catalytic Anionic Site (CAS)

Toxins ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 389 ◽  
Author(s):  
Joyce de Almeida ◽  
Rafael Dolezal ◽  
Ondrej Krejcar ◽  
Kamil Kuca ◽  
Kamil Musilek ◽  
...  
Keyword(s):  
Aflatoxin B1 ◽  
Binding Sites ◽  
Mixed Type ◽  
Experimental Studies ◽  
Common Type ◽  
Binding Modes ◽  
Anionic Site ◽  
Chronic Effects ◽  
Molecular Modeling Studies ◽  
Acute And Chronic Effects

The most common type of aflatoxin (AFT) found in nature is aflatoxin B1 (AFB1). This micotoxin is extremely hepatotoxic and carcinogenic to mammals, with acute and chronic effects. It is believed that this could be related to the capacity of AFB1 and its metabolites in inhibiting the enzyme acetylcholinesterase (AChE). In a previous work, we performed an inedited theoretical investigation on the binding modes of these molecules on the peripheral anionic site (PAS) of human AChE (HssAChE), revealing that the metabolites can also bind in the PAS in the same way as AFB1. Here, we investigated the binding modes of these compounds on the catalytic anionic site (CAS) of HssAChE to compare the affinity of the metabolites for both binding sites as well as verify which is the preferential one. Our results corroborated with experimental studies pointing to AFB1 and its metabolites as mixed-type inhibitors, and pointed to the residues relevant for the stabilization of these compounds on the CAS of HssAChE.

Corrigendum

2019 ◽  
Vol 26 (3) ◽  
pp. 235-235
Keyword(s):  
Review Article ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches

In the Review Article entitled “An Emerging Role of Endometrial Inflammasome in Reproduction: New Therapeutic Approaches” published in Protein & Peptides Letters, 2018, Vol. 26, No. 5, the affiliations of authors are revised due to recent restructuring that took place within the Institution for which the authors work for. The revised affiliation is as follows: </p><p> Fiorella Di Nicuoloa,b,*, Monia Specchiac, Lorenza Trentavizic, Alfredo Pontecorvid, Giovanni Scambiacc,e and Nicoletta Di Simoneb,c </p><p> aIstituto Scientifico Internazionale Paolo VI, ISI, Università Cattolica del Sacro Cuore, Rome, Italia; bFondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Ostetricia e Patologia Ostetrica, Dipartimento di Scienze della Salute della Donna e del Bambino, Roma, Italia; cUniversità Cattolica del Sacro Cuore, Istituto di Clinica Ostetrica e Ginecologica, Roma, Italia; dFondazione Policlinico Universitario A. Gemelli IRCCS, Dipartimento di Scienze Gastroenterologiche, Endocrino- Metaboliche e Nefro-Urologiche, Roma, Italia; eFondazione Policlinico Universitario A. Gemelli IRCCS, U.O.C. di Ginecologia Oncologica, Dipartimento di Scienze della Salute della Donna e del Bambino, Roma, Italia

scholarly journals Medicinal Plants from Brazilian Cerrado: Antioxidant and Anticancer Potential and Protection against Chemotherapy Toxicity

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
José Tarcísio de Giffoni de Carvalho ◽  
Débora da Silva Baldivia ◽  
Daniel Ferreira Leite ◽  
Laura Costa Alves de Araújo ◽  
Priscilla Pereira de Toledo Espindola ◽  
...  
Keyword(s):  
Cell Death ◽  
Medicinal Plants ◽  
Antioxidant Properties ◽  
Natural Antioxidants ◽  
Review Article ◽  
Malignant Cells ◽  
Cell Toxicity ◽  
Brazilian Cerrado ◽  
Therapeutic Approaches ◽  
Chemotherapy Toxicity

The use of natural antioxidants in cancer therapy has increased: first, due to the potential of natural antioxidants to kill tumour cells and second, because of their capacity to protect healthy cells from the damage caused by chemotherapy. This review article discusses the antioxidant properties of extracts obtained from medicinal plants from the Brazilian Cerrado and the cell death profile induced by each of these extracts in malignant cells. Next, we describe the capacity of other medicinal plants from the Cerrado to protect against chemotherapy-induced cell toxicity. Finally, we focus on recent insights into the cell death profile induced by extracts from Cerrado plants and perspectives for future therapeutic approaches.

Sign in / Sign up

Export Citation Format

Share Document