Search

Over 750 million cases of COVID-19, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), have been reported since the onset of the global outbreak. The need for effective treatments has spurred intensive research for therapeutic agents based on pharmaceutical repositioning or natural products. In light of prior studies asserting the bioactivity of natural compounds of the autochthonous Peruvian flora, the present study focuses on the identification SARS-CoV-2 Mpro main protease dimer inhibitors. To this end, a target-based virtual screening was performed over a representative set of Peruvian flora-derived natural compounds. The best poses obtained from the ensemble molecular docking process were selected. These structures were subjected to extensive molecular dynamics steps for the computation of binding free energies along the trajectory and evaluation of the stability of the complexes. The compounds exhibiting the best free energy behaviors were selected for in vitro testing, confirming the inhibitory activity of Hyperoside against Mpro, with a Ki value lower than 20 µM, presumably through allosteric modulation.

Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions.

Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions.

Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions.

Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions.

Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions.

Background: Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective for all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), for which the mechanism remains obscure and therapy is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with the non-structural (NS) HCV proteins NS5B and NS3/NS4A, indicating a role in HCC tumorigenesis and effect on DAA therapy. Methods: Surface plasmon resonance biosensor technology was used to characterize direct interactions between AnxA2 and HCV NS5B, NS3/NS4 and RNA, and the subsequent effects on catalysis and inhibition. Results: No direct interaction between AnxA2 and NS3/NS4A was detected, while AnxA2 formed a slowly dissociating, high affinity (K D = 30 nM), complex with NS5B, decreasing its catalytic activity and affinity for the allosteric inhibitor filibuvir. The RNA binding of the two proteins was independent and AnxA2 and NS5B interacted with different RNAs in ternary complexes of AnxA2:NS5B:RNA, indicating specific preferences. Conclusions: The complex interplay revealed between NS5B, AnxA2, RNA and filibuvir, suggests that AnxA2 may have an important role for the progression and treatment of HCV infections and the development of HCC, which should be considered also when designing new allosteric inhibitors.

Background: Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective for all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), for which the mechanism remains obscure and therapy is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with the non-structural (NS) HCV proteins NS5B and NS3/NS4A, indicating a role in HCC tumorigenesis and effect on DAA therapy. Methods: Surface plasmon resonance biosensor technology was used to characterize direct interactions between AnxA2 and HCV NS5B, NS3/NS4 and RNA, and the subsequent effects on catalysis and inhibition. Results: No direct interaction between AnxA2 and NS3/NS4A was detected, while AnxA2 formed a slowly dissociating, high affinity (K D = 30 nM), complex with NS5B, decreasing its catalytic activity and affinity for the allosteric inhibitor filibuvir. The RNA binding of the two proteins was independent and AnxA2 and NS5B interacted with different RNAs in ternary complexes of AnxA2:NS5B:RNA, indicating specific preferences. Conclusions: The complex interplay revealed between NS5B, AnxA2, RNA and filibuvir, suggests that AnxA2 may have an important role for the progression and treatment of HCV infections and the development of HCC, which should be considered also when designing new allosteric inhibitors.

Background: Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective for all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), for which the mechanism remains obscure and therapy is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with the non-structural (NS) HCV proteins NS5B and NS3/NS4A, indicating a role in HCC tumorigenesis and effect on DAA therapy. Methods: Surface plasmon resonance biosensor technology was used to characterize direct interactions between AnxA2 and HCV NS5B, NS3/NS4 and RNA, and the subsequent effects on catalysis and inhibition. Results: No direct interaction between AnxA2 and NS3/NS4A was detected, while AnxA2 formed a slowly dissociating, high affinity (K D = 30 nM), complex with NS5B, decreasing its catalytic activity and affinity for the allosteric inhibitor filibuvir. The RNA binding of the two proteins was independent and AnxA2 and NS5B interacted with different RNAs in ternary complexes of AnxA2:NS5B:RNA, indicating specific preferences. Conclusions: The complex interplay revealed between NS5B, AnxA2, RNA and filibuvir, suggests that AnxA2 may have an important role for the progression and treatment of HCV infections and the development of HCC, which should be considered also when designing new allosteric inhibitors.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B(PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotropic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogensis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogensis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B(PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotropic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogensis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogensis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B(PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotropic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogensis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogensis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B(PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotropic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogensis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogensis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B(PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotropic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogensis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogensis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B(PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotropic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogensis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogensis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B(PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotropic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogensis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogensis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

Background: Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective for all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), for which the mechanism remains obscure and therapy is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with the non-structural (NS) HCV proteins NS5B and NS3/NS4A, indicating a role in HCC tumorigenesis and effect on DAA therapy. Methods: Surface plasmon resonance biosensor technology was used to characterize direct interactions between AnxA2 and HCV NS5B, NS3/NS4 and RNA, and the subsequent effects on catalysis and inhibition. Results: No direct interaction between AnxA2 and NS3/NS4A was detected, while AnxA2 formed a slowly dissociating, high affinity (K D = 30 nM), complex with NS5B, decreasing its catalytic activity and affinity for the allosteric inhibitor filibuvir. The RNA binding of the two proteins was independent and AnxA2 and NS5B interacted with different RNAs in ternary complexes of AnxA2:NS5B:RNA, indicating specific preferences. Conclusions: The complex interplay revealed between NS5B, AnxA2, RNA and filibuvir, suggests that AnxA2 may have an important role for the progression and treatment of HCV infections and the development of HCC, which should be considered also when designing new allosteric inhibitors.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B(PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotropic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogensis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogensis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

Background: Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective for all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), for which the mechanism remains obscure and therapy is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with the non-structural (NS) HCV proteins NS5B and NS3/NS4A, indicating a role in HCC tumorigenesis and effect on DAA therapy. Methods: Surface plasmon resonance biosensor technology was used to characterize direct interactions between AnxA2 and HCV NS5B, NS3/NS4 and RNA, and the subsequent effects on catalysis and inhibition. Results: No direct interaction between AnxA2 and NS3/NS4A was detected, while AnxA2 formed a slowly dissociating, high affinity (K D = 30 nM), complex with NS5B, decreasing its catalytic activity and affinity for the allosteric inhibitor filibuvir. The RNA binding of the two proteins was independent and AnxA2 and NS5B interacted with different RNAs in ternary complexes of AnxA2:NS5B:RNA, indicating specific preferences. Conclusions: The complex interplay revealed between NS5B, AnxA2, RNA and filibuvir, suggests that AnxA2 may have an important role for the progression and treatment of HCV infections and the development of HCC, which should be considered also when designing new allosteric inhibitors.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B(PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotropic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogensis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogensis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B(PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotropic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogensis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogensis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B (PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotrophic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogenesis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogenesis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B (PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotrophic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogenesis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogenesis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.

An impaired synaptogenesis is known to be a common neuropathology in a number of severe mental disorders including schizophrenia, Parkinson disease, bipolar and dementia. Protein tyrosine phosphatase 1B (PTP1B) has been reported to impair neurite outgrowth and synaptic formation via attenuating Brain-derived neurotrophic factor (BDNF)-mediated signalling. Leptin signalling also facilitates BDNF and promotes synaptogenesis which is inhibited by PTP1B. Therefore PTP1B is a potential drug target to reverse BDNF-mediated neurogenesis. In this study, lupane triterpenes, a cluster of natural products, are determined as novel PTP1B allosteric inhibitors which inhibit PTP1B with strong potency and selectivity. Lupane triterpenes inhibit psychotomimetic drug-induced PTP1B and reverse PTP1B-caused BDNF reduction and neurogenesis impairment, indicating that lupane triterpenes are potential drug candidates for PTP1B inhibition and PTP1B-related neurological disorders.