scholarly journals Structural basis of the differential binding of engineered knottins 2.5F and 2.5D to integrins αVβ3 and α5β1

2019 ◽  
Author(s):  
Johannes F. Van Agthoven ◽  
Hengameh Shams ◽  
Frank V. Cochran ◽  
José L. Alonso ◽  
James R. Kintzing ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Critical Role ◽  
Md Simulations ◽  
Structural Basis ◽  
Conformational Selection ◽  
Drug Candidates ◽  
Tumor Survival ◽  
Differential Binding ◽  
Integrin Ligand

AbstractIntegrins αVβ3 and α5β1 play critical roles in tumor survival, invasion, metastasis, and angiogenesis and are validated targets for cancer therapy and molecular imaging. Increasing evidence suggests that targeting both integrins simultaneously with antagonists is more effective in cancer therapy because of concerns about resistance and paradoxical promotion of tumor growth with use of agents highly selective for a single integrin. Engineered Arg-Gly-Asp (RGD)-containing 3.5 kDa cysteine-knot proteins (knottins 2.5F and 2.5D) are attractive drug candidates due to their exceptional structural stability and high affinity binding to certain integrins. 2.5F binds both αVβ3 and α5β1, whereas 2.5D is αVβ3-selective. To elucidate the structural basis of integrin selection, we determined the structures of 2.5F and 2.5D both as apo-proteins and in complex with αVβ3. These data, combined with MD simulations and mutational studies, revealed a critical role of two αVβ3-specific residues in the vicinity of the metal ion dependent adhesion site (MIDAS) in promoting an αVβ3-induced fit of 2.5D. In contrast, conformational selection accounted for the specificity of 2.5F to both integrins. These data provide new insights into the structural basis of integrin-ligand binding specificity, and could help in development of integrin-targeted therapeutics.

scholarly journals Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy

2019 ◽  
Vol 20 (9) ◽  
pp. 2241 ◽  
Author(s):  
Debarati Banik ◽  
Sara Moufarrij ◽  
Alejandro Villagra
Keyword(s):  
Histone Deacetylase Inhibitors ◽  
Critical Role ◽  
Preclinical Studies ◽  
Clinical Use ◽  
Combination Therapies ◽  
Drug Candidates ◽  
Cellular Processes ◽  
Fda Approval

Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration. Finally, we have included examples of ongoing trials for each of the above categories of HDACis as standalone agents or in combination with immunotherapeutic approaches.

Metabolite identification in preclinical and clinical phase of drug development

2021 ◽  
Vol 22 ◽  
Author(s):  
Yali Wu ◽  
Lulu Pan ◽  
Zhendong Chen ◽  
Yuandong Zheng ◽  
Xingxing Diao ◽  
...  
Keyword(s):  
Drug Development ◽  
Kinase Inhibitors ◽  
Critical Role ◽  
Metabolite Identification ◽  
Correct Identification ◽  
Drug Candidates ◽  
Clinical Phase ◽  
Natural Medicines ◽  
Insight Into

: Metabolite identification plays a critical role in the phases during drug development. Drug metabolites can contribute to efficacy, toxicity, and drug-drug interaction. Thus, the correct identification of metabolites is essential to understand the behavior of drugs in humans. Drug administration authorities (e.g., FDA, EMA, and NMPA) emphasize evaluating the safety of human metabolites with exposure higher than 10% of the total drug-related components. Many previous reviews have summarized the various methods, tools, and strategies for the appropriate and comprehensive identification of metabolites. In this review, we focus on summarizing the importance of identifying metabolites in the preclinical and clinical phases of drug development. Summarized scenarios include the role of metabolites in pharmacokinetics/pharmacodynamics (PK/PD) analysis, disproportional exposure of metabolites that contribute to drug toxicity, changes in metabolite exposure in renal-impaired patients, covalent tyrosine kinase inhibitors (anticancer drugs), and metabolite identification of drug candidates from natural medicines. This review is aimed to provide meaningful insight into the significant role of metabolite identification in drug development.

scholarly journals Structural basis of the heterodimerization of the MST and RASSF SARAH domains in the Hippo signalling pathway

2014 ◽  
Vol 70 (7) ◽  
pp. 1944-1953 ◽  
Author(s):  
Eunha Hwang ◽  
Hae-Kap Cheong ◽  
Ameeq Ul Mushtaq ◽  
Hye-Yeon Kim ◽  
Kwon Joo Yeo ◽  
...  
Keyword(s):  
Structural Information ◽  
Critical Role ◽  
Three Dimensional ◽  
Helical Structure ◽  
Structural Features ◽  
Signalling Pathway ◽  
Structural Basis ◽  
X Ray Crystallography ◽  
Hippo Signalling

Despite recent progress in research on the Hippo signalling pathway, the structural information available in this area is extremely limited. Intriguingly, the homodimeric and heterodimeric interactions of mammalian sterile 20-like (MST) kinases through the so-called `SARAH' (SAV/RASSF/HPO) domains play a critical role in cellular homeostasis, dictating the fate of the cell regarding cell proliferation or apoptosis. To understand the mechanism of the heterodimerization of SARAH domains, the three-dimensional structures of an MST1–RASSF5 SARAH heterodimer and an MST2 SARAH homodimer were determined by X-ray crystallography and were analysed together with that previously determined for the MST1 SARAH homodimer. While the structure of the MST2 homodimer resembled that of the MST1 homodimer, the MST1–RASSF5 heterodimer showed distinct structural features. Firstly, the six N-terminal residues (Asp432–Lys437), which correspond to the short N-terminal 310-helix h1 kinked from the h2 helix in the MST1 homodimer, were disordered. Furthermore, the MST1 SARAH domain in the MST1–RASSF5 complex showed a longer helical structure (Ser438–Lys480) than that in the MST1 homodimer (Val441–Lys480). Moreover, extensive polar and nonpolar contacts in the MST1–RASSF5 SARAH domain were identified which strengthen the interactions in the heterodimer in comparison to the interactions in the homodimer. Denaturation experiments performed using urea also indicated that the MST–RASSF heterodimers are substantially more stable than the MST homodimers. These findings provide structural insights into the role of the MST1–RASSF5 SARAH domain in apoptosis signalling.

scholarly journals Structural Basis for Differential Binding of the Interleukin-8 Monomer and Dimer to the CXCR1 N-Domain: Role of Coupled Interactions and Dynamics

Biochemistry ◽  
2009 ◽  
Vol 48 (37) ◽  
pp. 8795-8805 ◽  
Author(s):  
Aishwarya Ravindran ◽  
Prem Raj B. Joseph ◽  
Krishna Rajarathnam
Keyword(s):  
Interleukin 8 ◽  
Structural Basis ◽  
Differential Binding

scholarly journals Nanotechnology-Based Drug Delivery to Improve the Therapeutic Benefits of NRF2 Modulators in Cancer Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 685
Author(s):  
Zerrin Sezgin-Bayindir ◽  
Sonia Losada-Barreiro ◽  
Carlos Bravo-Díaz ◽  
Matej Sova ◽  
Julijana Kristl ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Cancer Therapy ◽  
Drug Delivery Systems ◽  
Critical Role ◽  
Delivery Systems ◽  
Related Factor ◽  
New Horizons ◽  
Therapeutic Benefits ◽  
Anticancer Treatment

The disadvantages of conventional anticancer drugs, such as their low bioavailability, poor targeting efficacy, and serious side effects, have led to the discovery of new therapeutic agents and potential drug delivery systems. In particular, the introduction of nano-sized drug delivery systems (NDDSs) has opened new horizons for effective cancer treatment. These are considered potential systems that provide deep tissue penetration and specific drug targeting. On the other hand, nuclear factor erythroid 2-related factor 2 (NRF2)-based anticancer treatment approaches have attracted tremendous attention and produced encouraging results. However, the lack of effective formulation strategies is one of the factors that hinder the clinical application of NRF2 modulators. In this review, we initially focus on the critical role of NRF2 in cancer cells and NRF2-based anticancer treatment. Subsequently, we review the preparation and characterization of NDDSs encapsulating NRF2 modulators and discuss their potential for cancer therapy.

scholarly journals Autophagy and Its Role in Protein Secretion: Implications for Cancer Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Israel Cotzomi-Ortega ◽  
Patricia Aguilar-Alonso ◽  
Julio Reyes-Leyva ◽  
Paola Maycotte
Keyword(s):  
Cancer Therapy ◽  
Cancer Progression ◽  
Protein Secretion ◽  
Survival Function ◽  
Degradation Pathway ◽  
Intercellular Signaling ◽  
Tumor Survival ◽  
Response To Stress ◽  
Secretion Pathways

Autophagy is a protein and organelle degradation pathway important for the maintenance of cytoplasmic homeostasis and for providing nutrients for survival in response to stress conditions. Recently, autophagy has been shown to be important for the secretion of diverse proteins involved in inflammation, intercellular signaling, and cancer progression. The role of autophagy in cancer depends on the stage of tumorigenesis, serving a tumor-suppressor role before transformation and a tumor-survival function once a tumor is established. We review recent evidence demonstrating the complexity of autophagy regulation during cancer, considering the interaction of autophagy with protein secretion pathways. Autophagy manipulation during cancer treatment is likely to affect protein secretion andinter-cellular signaling either to the neighboring cancer cells or to the antitumoral immune response. This will be an important consideration during cancer therapy since several clinical trials are trying to manipulate autophagy in combination with chemotherapy for the treatment of diverse types of cancers.

scholarly journals Dual role of strigolactone receptor signaling partner in inhibiting substrate hydrolysis

2021 ◽  
Author(s):  
Briana L Sobecks ◽  
Jiming Chen ◽  
Diwakar Shukla
Keyword(s):  
Active Site ◽  
Conformational Stability ◽  
Critical Role ◽  
Md Simulations ◽  
Binding Pocket ◽  
Conformational Ensemble ◽  
Downstream Signaling ◽  
F Box Protein ◽  
Substrate Hydrolysis

Plant branch and root growth relies on metabolism of the strigolactone (SL) hormone. The interaction between the SL molecule, Oryza sativa DWARF14 (D14) SL receptor, and D3 F-box protein has been shown to play a critical role in SL perception. Previously, it was believed that D3 only interacts with the closed form of D14 to induce downstream signaling, but recent experiments indicate that D3, as well as its C-terminal helix (CTH), can interact with the open form as well to inhibit strigolactone signaling. Two hypotheses for the CTH induced inhibition are that either the CTH affects the conformational ensemble of D14 by stabilizing catalytically inactive states, or the CTH interacts with SLs in a way that prevents them from entering the binding pocket. In this study, we have performed molecular dynamics (MD) simulations to assess the validity of these hypotheses. We used an apo system with only D14 and the CTH to test the active site conformational stability and a holo system with D14, the CTH, and an SL molecule to test the interaction between the SL and CTH. Our simulations show that the CTH affects both active site conformation and the ability of SLs to move into the binding pocket. In the apo system, the CTH allosterically stabilized catalytic residues into their inactive conformation. In the holo system, significant interactions between SLs and the CTH hindered the ability of SLs to enter the D14 binding pocket. These two mechanisms account for the observed decrease in SL binding to D14 and subsequent ligand hydrolysis in the presence of the CTH.

Critical Role of Confinement in the NMR Surface Relaxation and Diffusion of n-Heptane in a Polymer Matrix Revealed by MD Simulations

2020 ◽  
Vol 124 (18) ◽  
pp. 3801-3810 ◽  
Author(s):  
Arjun Valiya Parambathu ◽  
Philip M. Singer ◽  
George J. Hirasaki ◽  
Walter G. Chapman ◽  
Dilipkumar Asthagiri
Keyword(s):  
Polymer Matrix ◽  
Critical Role ◽  
Md Simulations ◽  
Surface Relaxation ◽  
And Diffusion

scholarly journals Role of Myeloid Cells in Oncolytic Reovirus-Based Cancer Therapy

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 654
Author(s):  
Vishnupriyan Kumar ◽  
Michael A. Giacomantonio ◽  
Shashi Gujar
Keyword(s):  
T Cell ◽  
Cancer Therapy ◽  
Critical Role ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Antitumor Effects ◽  
Cell Responses ◽  
Combination Strategies ◽  
Cell Immunity

Oncolytic reovirus preferentially targets and kills cancer cells via the process of oncolysis, and additionally drives clinically favorable antitumor T cell responses that form protective immunological memory against cancer relapse. This two-prong attack by reovirus on cancers constitutes the foundation of its use as an anticancer oncolytic agent. Unfortunately, the efficacy of these reovirus-driven antitumor effects is influenced by the highly suppressive tumor microenvironment (TME). In particular, the myeloid cell populations (e.g., myeloid-derived suppressive cells and tumor-associated macrophages) of highly immunosuppressive capacities within the TME not only affect oncolysis but also actively impair the functioning of reovirus-driven antitumor T cell immunity. Thus, myeloid cells within the TME play a critical role during the virotherapy, which, if properly understood, can identify novel therapeutic combination strategies potentiating the therapeutic efficacy of reovirus-based cancer therapy.

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