Skeletal function and structure: Implications for tissue-targeted therapeutics

2005 ◽  
Vol 57 (7) ◽  
pp. 945-957 ◽  
Author(s):  
J SHEA ◽  
S MILLER
Keyword(s):  
Targeted Therapeutics ◽  
Skeletal Function

Targeting Membrane Receptors of Ovarian Cancer Cells for Therapy

2019 ◽  
Vol 19 (6) ◽  
pp. 449-467
Author(s):  
Zhiquan Liang ◽  
Ziwen Lu ◽  
Yafei Zhang ◽  
Dongsheng Shang ◽  
Ruyan Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Receptor Binding ◽  
Cytoreductive Surgery ◽  
Therapeutic Strategies ◽  
Membrane Receptors ◽  
Ovarian Cancer Cells ◽  
Advanced Stage ◽  
Targeted Therapeutics ◽  
Cellular Processes

Ovarian cancer is a leading cause of death worldwide from gynecological malignancies, mainly because there are few early symptoms and the disease is generally diagnosed at an advanced stage. In addition, despite the effectiveness of cytoreductive surgery for ovarian cancer and the high response rates to chemotherapy, survival has improved little over the last 20 years. The management of patients with ovarian cancer also remains similar despite studies showing striking differences and heterogeneity among different subtypes. It is therefore clear that novel targeted therapeutics are urgently needed to improve clinical outcomes for ovarian cancer. To that end, several membrane receptors associated with pivotal cellular processes and often aberrantly overexpressed in ovarian cancer cells have emerged as potential targets for receptor-mediated therapeutic strategies including specific agents and multifunctional delivery systems based on ligand-receptor binding. This review focuses on the profiles and potentials of such strategies proposed for ovarian cancer treatment and imaging.

Monocyclic Peptides: Types, Synthesis and Applications

2020 ◽  
Vol 22 (1) ◽  
pp. 123-135 ◽  
Author(s):  
Yalda Khazaei-poul ◽  
Shohreh Farhadi ◽  
Sepideh Ghani ◽  
Safar Ali Ahmadizad ◽  
Javad Ranjbari
Keyword(s):  
Drug Delivery ◽  
Cyclic Peptides ◽  
Rational Design ◽  
Bioactive Molecules ◽  
Synthesis Methods ◽  
Targeted Therapeutics ◽  
Diagnostic Agents ◽  
Linear Types ◽  
Microbial Agents ◽  
Structural Classes

: Peptides are considered to be appropriate tools in various biological fields. They can be primarily used for the rational design of bioactive molecules. They can act as ligands in the development of targeted therapeutics as well as diagnostics, can be used in the design of vaccines or can be employed in agriculture. Peptides can be classified in two broad structural classes: linear and cyclic peptides. Monocyclic peptides are a class of polypeptides with one macrocyclic ring that bears advantages, such as more selective binding and uptake by the target receptor, as well as higher potency and stability compared to linear types. This paper provides an overview of the categories, synthesis methods and various applications of cyclic peptides. The various applications of cyclic peptides include their use as pro-apoptotic and anti-microbial agents, their application as targeting ligands in drug delivery and diagnostic agents, as well as agricultural and therapeutics applications that are elaborated and discussed in this paper.

scholarly journals Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

2020 ◽  
Vol 12 ◽  
pp. 175883592092006
Author(s):  
Hang-Ping Yao ◽  
Sreedhar Reddy Suthe ◽  
Xiang-Min Tong ◽  
Ming-Hai Wang
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Targeted Therapeutics ◽  
Antibody Drug Conjugates ◽  
Drug Candidates ◽  
Drug Conjugates ◽  
Ron Receptor ◽  
Antibody Drug

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

scholarly journals Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 433
Author(s):  
Bijesh George ◽  
P. Mukundan Pillai ◽  
Aswathy Mary Paul ◽  
Revikumar Amjesh ◽  
Kim Leitzel ◽  
...  
Keyword(s):  
Drug Targets ◽  
Target Genes ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Survival Duration ◽  
Cancer Drug ◽  
Targeted Therapeutics ◽  
Cellular Targets ◽  
Human Cancer Cells ◽  
Cancer Types

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

scholarly journals Blastic plasmacytoid dendritic cell neoplasm with genetic mutations in multiple epigenetic modifiers: a case report

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052098266
Author(s):  
Xinmei Dang ◽  
Di Zhou ◽  
Lingjun Meng ◽  
Lintao Bi
Keyword(s):  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Genetic Mutations ◽  
Cell Surface Markers ◽  
Targeted Therapeutics ◽  
Genetic Studies ◽  
Clinical Prognosis ◽  
Epigenetic Modifiers ◽  
Cell Neoplasm ◽  
Underlying Pathogenesis

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematodermic malignancy derived from plasmacytoid dendritic cell precursors. Despite advances in our understanding of tumor cell surface markers, the pathogenesis of BPDCN remains largely unknown. No standard or optimal treatments are available for BPDCN, and the prognosis is usually poor. We report herein a case of BPDCN that harbored multiple genetic mutations in epigenetic modifiers such as TET2 and ZRSR2. Genetic studies in patients with BPDCN may provide insights into the underlying pathogenesis, prediction of clinical prognosis, and development of better targeted therapeutics for this rare clinical entity.

scholarly journals Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn’s Disease

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1349
Author(s):  
Kibrom M. Alula ◽  
Dakota N. Jackson ◽  
Andrew D. Smith ◽  
Daniel S. Kim ◽  
Kevin Turner ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Lipid Metabolism ◽  
Crohn's Disease ◽  
Paneth Cell ◽  
Mitochondrial Damage ◽  
Paneth Cells ◽  
Cell Phenotype ◽  
Type I ◽  
Targeted Therapeutics ◽  
Gene Signatures

Paneth cell defects in Crohn’s disease (CD) patients (called the Type I phenotype) are associated with worse clinical outcomes. Recent studies have implicated mitochondrial dysfunction in Paneth cells as a mediator of ileitis in mice. We hypothesized that CD Paneth cells exhibit impaired mitochondrial health and that mitochondrial-targeted therapeutics may provide a novel strategy for ileal CD. Terminal ileal mucosal biopsies from adult CD and non-IBD patients were characterized for Paneth cell phenotyping and mitochondrial damage. To demonstrate the response of mitochondrial-targeted therapeutics in CD, biopsies were treated with vehicle or Mito-Tempo, a mitochondrial-targeted antioxidant, and RNA transcriptome was analyzed. During active CD inflammation, the epithelium exhibited mitochondrial damage evident in Paneth cells, goblet cells, and enterocytes. Independent of inflammation, Paneth cells in Type I CD patients exhibited mitochondrial damage. Mito-Tempo normalized the expression of interleukin (IL)-17/IL-23, lipid metabolism, and apoptotic gene signatures in CD patients to non-IBD levels. When stratified by Paneth cell phenotype, the global tissue response to Mito-Tempo in Type I patients was associated with innate immune, lipid metabolism, and G protein-coupled receptor (GPCR) gene signatures. Targeting impaired mitochondria as an underlying contributor to inflammation provides a novel treatment approach for CD.

scholarly journals Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ayushi Chaurasiya ◽  
Swati Garg ◽  
Ashish Khanna ◽  
Chintam Narayana ◽  
Ved Prakash Dwivedi ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Malaria Parasite ◽  
Host Cells ◽  
Nicotinamide Adenine ◽  
Targeted Therapeutics ◽  
Nad Metabolism ◽  
Host Cell Death ◽  
Nanomolar Range

AbstractHijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.

scholarly journals Chikungunya and Zika Viruses: Co-Circulation and the Interplay between Viral Proteins and Host Factors

Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 448
Author(s):  
Sineewanlaya Wichit ◽  
Nuttamonpat Gumpangseth ◽  
Rodolphe Hamel ◽  
Sakda Yainoy ◽  
Siwaret Arikit ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
Virus Transmission ◽  
Antiviral Agent ◽  
Viral Proteins ◽  
Targeted Therapeutics ◽  
Limited Information ◽  
Mosquito Vectors ◽  
Host Proteins ◽  
Host Interactions ◽  
Viral Host Interactions

Chikungunya and Zika viruses, both transmitted by mosquito vectors, have globally re-emerged over for the last 60 years and resulted in crucial social and economic concerns. Presently, there is no specific antiviral agent or vaccine against these debilitating viruses. Understanding viral–host interactions is needed to develop targeted therapeutics. However, there is presently limited information in this area. In this review, we start with the updated virology and replication cycle of each virus. Transmission by similar mosquito vectors, frequent co-circulation, and occurrence of co-infection are summarized. Finally, the targeted host proteins/factors used by the viruses are discussed. There is an urgent need to better understand the virus–host interactions that will facilitate antiviral drug development and thus reduce the global burden of infections caused by arboviruses.

scholarly journals Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Suxing Liu ◽  
Dong Liu ◽  
Ru Shen ◽  
Di Li ◽  
Qiyue Hu ◽  
...  
Keyword(s):  
Topical Treatment ◽  
Clinical Success ◽  
Systemic Exposure ◽  
Skin Inflammation ◽  
Targeted Therapeutics ◽  
High Exposure ◽  
Structure Activity ◽  
Potential Safety ◽  
Systematic Structure ◽  
And Function

AbstractClinical success of IL-17/IL-23 pathway biologics for the treatment of moderate to severe psoriasis suggests that targeting RORγt, a master regulator for the proliferation and function of Th17 cells, could be an effective alternative. However, oral RORγ antagonists (VTP43742, TAK828) with high systemic exposure showed toxicity in phase I/II clinical trials and terminated development. To alleviate the potential safety concerns, identifying compounds with skin-restricted exposure amenable for topical use is of great interest. Systematic structure activity relationship study and multi-parameter optimization led to the discovery of a novel RORγ antagonist (SHR168442) with desired properties for a topical drug. It suppressed the transcription of IL-17 gene, leading to reduction of IL-17 cytokine secretion. It showed high exposure in skin, but low in plasma. Topical application of SHR168442 in Vaseline exhibited excellent efficacy in the imiquimod-induced and IL-23-induced psoriasis-like skin inflammation mouse models and correlated with the reduction of Th17 pathway cytokines, IL-6, TNFα and IL-17A. This work demonstrated restricted skin exposure of RORγ antagonist may provide a new topical treatment option as targeted therapeutics for mild to moderate psoriasis patients and may be suitable for the treatment of any other inflammatory disorders that are accessible locally.

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