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Theranostics 2019CD36, a scavenger receptor expressed in multiple cell types, mediates lipid uptake, immunological recognition, inflammation, molecular adhesion, and apoptosis. CD36 is a... (Review)
Review
CD36, a scavenger receptor expressed in multiple cell types, mediates lipid uptake, immunological recognition, inflammation, molecular adhesion, and apoptosis. CD36 is a transmembrane glycoprotein that contains several posttranslational modification sites and binds to diverse ligands, including apoptotic cells, thrombospondin-1 (TSP-1), and fatty acids (FAs). Beyond fueling tumor metastasis and therapy resistance by enhancing lipid uptake and FA oxidation, CD36 attenuates angiogenesis by binding to TSP-1 and thereby inducing apoptosis or blocking the vascular endothelial growth factor receptor 2 pathway in tumor microvascular endothelial cells. Moreover, CD36-driven lipid metabolic reprogramming and functions in tumor-associated immune cells lead to tumor immune tolerance and cancer development. Notable advances have been made in demonstrating the regulatory networks that govern distinct physiological properties of CD36, and this has identified targeting CD36 as a potential strategy for cancer treatment. Here, we provide an overview on the structure, regulation, ligands, functions, and clinical trials of CD36 in cancer.
Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; CD36 Antigens; Humans; Lipid Metabolism; Neoplasms; Oligopeptides; Signal Transduction
PubMed: 31410189
DOI: 10.7150/thno.36037 -
Chemical & Pharmaceutical Bulletin 2020Auristatins are important payloads used in antibody drug conjugates (ADCs), and the most well-known compound family member, monomethyl auristatin (MMAE), is used in two... (Review)
Review
Auristatins are important payloads used in antibody drug conjugates (ADCs), and the most well-known compound family member, monomethyl auristatin (MMAE), is used in two Food and Drug Administration (FDA)-approved ADCs, Adcetris and Polivy. Multiple other auristatin-based ADCs are currently being evaluated in human clinical trials and further studies on this class of molecule are underway by several academic and industrial research groups. Our group's main focus is to investigate the structure-activity relationships (SAR) of novel auristatins with the goal of applying these to next generation ADCs. Modifications of the auristatin backbone scaffold have been widely reported in the chemical literature focusing on the terminal subunits: P1 (N-terminus) and P5 (C-terminus). Our approach was to modulate the activity and hydrophilic character through modifications of the central subunits P2-P3-P4 and thorough SAR study on the P5 subunit. Novel hydrophilic auristatins were observed to have greater potency in vitro and displayed enhanced in vivo antitumor activity when conjugated via protease-cleavable linkers and delivered intracellularly. Analysis of ADC aggregation also indicated that novel hydrophilic payloads enabled the synthesis of high-drug-to-antibody ratio (DAR) ADCs that were resistant to aggregation. Modification of the central peptide subunits also resulted in auristatins with potent cytotoxic activity in vitro and these azide-modified auristatins contain a handle for linker attachment from the central portion of the auristatin backbone.
Topics: Aminobenzoates; Animals; Antineoplastic Agents; Cell Proliferation; Cell Survival; Humans; Hydrophobic and Hydrophilic Interactions; Immunoconjugates; Molecular Structure; Oligopeptides
PubMed: 32115527
DOI: 10.1248/cpb.c19-00853 -
Circulation Oct 2021The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains controversial.
METHODS
In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (composite of death, myocardial infarction, or stroke) through 12 months.
RESULTS
Because of slower-than-projected enrollment and fewer-than-projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From May 3, 2016, to April 16, 2020, a total of 545 patients from 113 sites across 12 countries were randomly selected. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease, and 20.4% had metastatic disease. A major adverse cardiovascular event occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) patients assigned to leuprolide (hazard ratio, 1.28 [95% CI, 0.59-2.79]; =0.53).
CONCLUSIONS
PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02663908.
Topics: Aged; Humans; Leuprolide; Male; Oligopeptides; Prospective Studies; Prostatic Neoplasms
PubMed: 34459214
DOI: 10.1161/CIRCULATIONAHA.121.056810 -
Molecular Cancer Therapeutics Apr 2023Monomethyl auristatin E (MMAE) is a potent tubulin inhibitor that is used as the payload for four FDA-approved antibody-drug conjugates (ADC). Deconjugated MMAE readily...
Monomethyl auristatin E (MMAE) is a potent tubulin inhibitor that is used as the payload for four FDA-approved antibody-drug conjugates (ADC). Deconjugated MMAE readily diffuses into untargeted cells, resulting in off-target toxicity. Here, we report the development and evaluation of a humanized Fab fragment (ABC3315) that enhances the therapeutic selectivity of MMAE ADCs. ABC3315 increased the IC50 of MMAE against human cancer cell lines by > 500-fold with no impact on the cytotoxicity of MMAE ADCs, including polatuzumab vedotin (PV) and trastuzumab-vc-MMAE (TvcMMAE). Coadministration of ABC3315 did not reduce the efficacy of PV or TvcMMAE in xenograft tumor models. Coadministration of ABC3315 with 80 mg/kg TvcMMAE significantly (P < 0.0001) increased the cumulative amount of MMAE that was excreted in urine 0 to 4 days after administration from 789.4±19.0 nanograms (TvcMMAE alone) to 2625±206.8 nanograms (for mice receiving TvcMMAE with coadministration of ABC3315). Mice receiving 80 mg/kg TvcMMAE and PBS exhibited a significant drop in white blood cell counts (P = 0.025) and red blood cell counts (P = 0.0083) in comparison with control mice. No significant differences, relative to control mice, were found for white blood cell counts (P = 0.15) or for red blood cell counts (P = 0.23) for mice treated with 80 mg/kg TvcMMAE and ABC3315. Coadministration of ABC3315 with 120 mg/kg PV significantly (P = 0.045) decreased the percentage body weight loss at nadir for treated mice from 11.9%±7.0% to 4.1%±2.1%. Our results demonstrate that ABC3315, an anti-MMAE Fab fragment, decreases off-target toxicity while not decreasing antitumor efficacy, increasing the therapeutic window of MMAE ADCs.
Topics: Humans; Animals; Mice; Immunoconjugates; Oligopeptides; Trastuzumab; Disease Models, Animal; Therapeutic Index; Cell Line, Tumor; Xenograft Model Antitumor Assays
PubMed: 36723609
DOI: 10.1158/1535-7163.MCT-22-0440 -
Marine Drugs Jan 2021Cyanobacteria are a rich source of secondary metabolites with a vast biotechnological potential. These compounds have intrigued the scientific community due their... (Review)
Review
Cyanobacteria are a rich source of secondary metabolites with a vast biotechnological potential. These compounds have intrigued the scientific community due their uniqueness and diversity, which is guaranteed by a rich enzymatic apparatus. The ribosomally synthesized and post-translationally modified peptides (RiPPs) are among the most promising metabolite groups derived from cyanobacteria. They are interested in numerous biological and ecological processes, many of which are entirely unknown. Microviridins are among the most recognized class of ribosomal peptides formed by cyanobacteria. These oligopeptides are potent inhibitors of protease; thus, they can be used for drug development and the control of mosquitoes. They also play a key ecological role in the defense of cyanobacteria against microcrustaceans. The purpose of this review is to systematically identify the key characteristics of microviridins, including its chemical structure and biosynthesis, as well as its biotechnological and ecological significance.
Topics: Animals; Cyanobacteria; Ecology; Humans; Insect Control; Oligopeptides; Protease Inhibitors
PubMed: 33406599
DOI: 10.3390/md19010017 -
International Journal of Molecular... Dec 2021Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as... (Review)
Review
Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as tolerance, addiction, respiratory depression, and cardiovascular events. This, in turn, can result in their overuse in cases of addiction, the need for dose escalation in cases of developing tolerance, and the emergence of dose-related opioid toxicity, resulting in respiratory depression or cardiovascular problems that can even lead to unintentional death. Therefore, a very important challenge for researchers is to look for ways to counteract the side effects of opioids. The use of peptides and their related compounds, which have been shown to modulate the effects of opioids, may provide such an opportunity. This short review is a compendium of knowledge about the most important and recent findings regarding selected peptides and their modulatory effects on various opioid actions, including cardiovascular and respiratory responses. In addition to the peptides more commonly reported in the literature in the context of their pro- and/or anti-opioid activity-such as neuropeptide FF (NPFF), cholecystokinin (CCK), and melanocyte inhibiting factor (MIF)-we also included in the review nociceptin/orphanin (N/OFQ), ghrelin, oxytocin, endothelin, and venom peptides.
Topics: Analgesics, Opioid; Animals; Cholecystokinin; Drug Tolerance; Ghrelin; Humans; Narcotic Antagonists; Oligopeptides; Opioid Peptides; Peptides; Receptors, Opioid; Nociceptin
PubMed: 34948415
DOI: 10.3390/ijms222413619 -
International Journal of Molecular... May 2020The COVID-19 global pandemic is caused by SARS-CoV-2, and represents an urgent medical and social issue. Unfortunately, there is still not a single proven effective drug... (Review)
Review
The COVID-19 global pandemic is caused by SARS-CoV-2, and represents an urgent medical and social issue. Unfortunately, there is still not a single proven effective drug available, and therefore, current therapeutic guidelines recommend supportive care including oxygen administration and treatment with antibiotics. Recently, patients have been also treated with off-label therapies which comprise antiretrovirals, anti-inflammatory compounds, antiparasitic agents and plasma from convalescent patients, all with controversial results. The ubiquitin-proteasome system (UPS) is important for the maintenance of cellular homeostasis, and plays a pivotal role in viral replication processes. In this review, we discuss several aspects of the UPS and the effects of its inhibition with particular regard to the life cycle of the coronaviruses (CoVs). In fact, proteasome inhibition by various chemical compounds, such as MG132, epoxomycin and bortezomib, may reduce the virus entry into the eucariotic cell, the synthesis of RNA, and the subsequent protein expression necessary for CoVs. Importantly, since UPS inhibitors reduce the cytokine storm associated with various inflammatory conditions, it is reasonable to assume that they might be repurposed for SARS-CoV-2, thus providing an additional tool to counteract both virus replication as well as its most deleterious consequences triggered by abnormal immunological response.
Topics: Antibodies, Monoclonal; Betacoronavirus; COVID-19; Coronavirus Infections; Endoplasmic Reticulum Stress; Humans; Oligopeptides; Pandemics; Pneumonia, Viral; Proteasome Inhibitors; SARS-CoV-2
PubMed: 32443911
DOI: 10.3390/ijms21103622 -
Journal of the... 2021Coronavirus disease 2019 (COVID-19) can occur due to contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has no confined treatment and,... (Review)
Review
Coronavirus disease 2019 (COVID-19) can occur due to contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has no confined treatment and, consequently, has high hospitalization and mortality rates. Moreover, people who contract COVID-19 present systemic inflammatory spillover. It is now known that COVID-19 pathogenesis is linked to the renin-angiotensin system (RAS). COVID-19 invades host cells via the angiotensin-converting enzyme 2 (ACE2) receptor-as such, an individual's susceptibility to COVID-19 increases alongside the upregulation of this receptor. COVID-19 has also been associated with interstitial pulmonary fibrosis, which leads to acute respiratory distress, cardiomyopathy, and shock. These outcomes are thought to result from imbalances in angiotensin (Ang) II and Ang-(1-7)/alamandine activity. ACE2, Ang-(1-7), and alamandine have potent anti-inflammatory properties, and some SARS-CoV-2 patients exhibit high levels of ACE2 and Ang-(1-7). This phenomenon could indicate a failing physiological response to prevent or reduce the severity of inflammation-mediated pulmonary injuries. Alamandine, which is another protective component of the RAS, has several health benefits owing to its antithrombogenic, anti-inflammatory, and antifibrotic characteristics. Alamandine alleviates pulmonary fibrosis via the Mas-related G protein-coupled receptor D (MrgD). Thus, a better understanding of this pathway could uncover novel pharmacological strategies for altering proinflammatory environments within the body. Following such strategies could inhibit fibrosis after SARS-CoV-2 infection and, consequently, prevent COVID-19.
Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Antiviral Agents; COVID-19; Humans; Oligopeptides; Peptide Fragments; Renin-Angiotensin System; COVID-19 Drug Treatment
PubMed: 34853605
DOI: 10.1155/2021/6824259 -
Chemistry (Weinheim An Der Bergstrasse,... Sep 2020Cyclic RGD peptides are well-known ligands of integrins. The integrins α β and α β are involved in angiogenesis, and integrin α β is abundantly present on cancer...
Cyclic RGD peptides are well-known ligands of integrins. The integrins α β and α β are involved in angiogenesis, and integrin α β is abundantly present on cancer cells, thus representing a therapeutic target. Hence, synthetic and biophysical studies continuously are being directed towards the understanding of ligand-integrin interaction. In this context, the development of versatile synthetic strategies to obtain fluorescent building blocks that can add molecular diversity and modular spectral characteristics while not compromising binding affinity or selectivity is a relevant task. An on-resin intramolecular Suzuki-Miyaura cross-coupling (SMC) between l- or d-7-bromotryptophan (7BrTrp) and a phenothiazine (Ptz) boronic acid affords fluorescent cyclic RGD pseudopeptides, c(RGD(W/w)Ptz). Ring closure by SMC establishes a phenothiazine-indole moiety with axial chirality. An array of eight novel compounds has been synthesized, among them one fluorescent compound with good affinity to integrin α β . The fluorescence properties of the analogues can be efficiently tuned depending on the substituents in Ptz moiety even for fluorescence emission in the visible (red) spectral range.
Topics: Fluorescence; Integrin alphaVbeta3; Ligands; Oligopeptides; Phenothiazines
PubMed: 32297686
DOI: 10.1002/chem.202001312 -
Science (New York, N.Y.) Oct 2020Protein kinases intrinsically sample a number of conformational states with distinct catalytic and binding activities. We used nuclear magnetic resonance spectroscopy to...
Protein kinases intrinsically sample a number of conformational states with distinct catalytic and binding activities. We used nuclear magnetic resonance spectroscopy to describe in atomic-level detail how Abl kinase interconverts between an active and two discrete inactive structures. Extensive differences in key structural elements between the conformational states give rise to multiple intrinsic regulatory mechanisms. The findings explain how oncogenic mutants can counteract inhibitory mechanisms to constitutively activate the kinase. Energetic dissection revealed the contributions of the activation loop, the Asp-Phe-Gly (DFG) motif, the regulatory spine, and the gatekeeper residue to kinase regulation. Characterization of the transient conformation to which the drug imatinib binds enabled the elucidation of drug-resistance mechanisms. Structural insight into inactive states highlights how they can be leveraged for the design of selective inhibitors.
Topics: Biocatalysis; Genes, abl; Humans; Imatinib Mesylate; Mutation; Nuclear Magnetic Resonance, Biomolecular; Oligopeptides; Protein Domains; Protein Kinase Inhibitors; Protein Structure, Secondary; Protein-Tyrosine Kinases
PubMed: 33004676
DOI: 10.1126/science.abc2754