Polyvalency: an emerging trend in the development of clinical antibodies.

Medicine has benefited greatly from the development of monoclonal antibody (mAb) technology. First-generation mAbs have seen significant success in the treatment of major diseases, such as autoimmune, inflammation, cancer, infectious, and cardiovascular diseases. Developing next-generation antibodies with improved potency, safety, and non-natural characteristics is a booming field of mAb research. In this review, we discuss the significance of polyvalency and polyvalent antibodies, as well as important findings from preclinical studies and clinical trials involving polyvalent antibodies. We then review the role of tumor necrosis factor-alpha (TNF-α) in inflammatory diseases and the need for polyvalent anti-TNF-α antibodies.

Engineered polyspecific antibodies: A new frontier in the field of immunotherapeutics.

The 21st-century beginning remarked with the huge success of monospecific MAbs, however, in the last couple of years, polyspecific MAbs (PsAbs) have been an interesting topic and show promise of being biobetter than monospecific MAbs. Polyspecificity, in which a single antibody serves multiple specific target binding, has been hypothesized to contribute to the development of a highly effective antibody repertoire for immune defence. This polyspecific MAb trend represents an explosion that is gripping the whole pharmaceutical industry. This review is concerned with the current development and quality enforcement of PsAbs. All provided literature on monospecific MAbs and polyspecific MAbs (PsAbs) were searched using various electronic databases such as PubMed, Google Scholar, Web of Science, Elsevier, Springer, ACS, Google Patent and books via the keywords Antibody engineering, Polyspecific antibody, Conventional antibody, non-conventional antibody, and Single domain antibody. In the literature, there are more than 100 different formats to construct PsAb by quadroma technology, chemical conjugation and genetic engineering. Till March 2023, nine PsAb have been approved around the world, and around 330 are in advanced developmental stages, showing the dominancy of PsAb in the growing health sector. Recent advancements in protein engineering techniques and the fusion of non-conventional antibodies have made it possible to create complex PsAbs that demonstrate higher stability and enhanced potency. This marks the most significant achievement for cancer immunotherapy, in which PsAbs have immense promise. It is worth mentioning that seven out of the nine PsAbs have been approved as anti-cancer therapy. As PsAbs continue to acquire prominence, they could pave the way for the development of novel immunotherapies for multiple diseases.

Polyspecificity - An emerging trend in the development of clinical antibodies.

The essence of the growth and development of therapeutic conventional monoclonal antibodies (MAbs) for the treatment of various disorders is the aptitude of MAbs to precisely bind a target antigen and neutralise or promote its activity. However, the conventional antibodies are monoclonal i.e., both paratopes bind to the same epitope. But most of the pathophysiological conditions are multifaceted, hence targeting/blocking/inhibition of more than one epitope/antigen is more promising than one epitope/antigen. Polyspecific antibodies (PsAbs) have the potential to concurrently bind to more than one target and are the next-generation antibodies that augment efficacy in both clinical and non-clinical contexts. Thus, the trend of engineering and developing various formats of PsAbs is emerging. In this review, we have briefly discussed the importance of antibody polyspecificity and PsAbs approved for clinical use. Subsequently, we have discussed the role of TNF-α and IL-23 in inflammatory diseases and stressed the need for developing anti-TNF-α and anti-IL-23 bispecific antibodies.

FDG PET/CT Aiding in Early Diagnosis of Central Pontine Myelinolysis.

ABSTRACT: We report a 70-year-old man with central pontine myelinolysis who presented in the emergency department with recent onset altered sensorium and tremors (Glasgow Coma Scale score, 13). Laboratory findings revealed hyponatremia and hypokalemia. MRI brain was unremarkable. Subsequently, patient was referred for FDG PET/CT to rule out malignancy or paraneoplastic syndrome. FDG PET revealed focal radiotracer uptake in the pons without any underlying CT abnormality consistent with central pontine myelinolysis, thus aiding in early diagnosis where conventional imaging modality was unremarkable.

Design and synthesis of pyrazolone-based compounds as potent blockers of SARS-CoV-2 viral entry into the host cells.

SARS-CoV-2 are enveloped positive-stranded RNA viruses that replicate in the cytoplasm. It relies on the fusion of their envelope with the host cell membrane to deliver their nucleocapsid into the host cell. The spike glycoprotein (S) mediates virus entry into cells via the human Angiotensin-converting enzyme 2 (hACE2) protein located on many cell types and tissues' outer surface. This study, therefore, aimed to design and synthesize novel pyrazolone-based compounds as potential inhibitors that would interrupt the interaction between the viral spike protein and the host cell receptor to prevent SARS-CoV 2 entrance into the cell. A series of pyrazolone compounds as potential SARS-CoV-2 inhibitors were designed and synthesized. Employing computational techniques, the inhibitory potentials of the designed compounds against both spike protein and hACE2 were evaluated. Results of the binding free energy from the in-silico analysis, showed that three compounds (7i, 7k and 8f) and six compounds (7b, 7h, 7k, 8d, 8g, and 8h) showed higher and better binding high affinity to SARS-CoV-2 Sgp and hACE-2, respectively compared to the standard drugs cefoperazone (CFZ) and MLN-4760. Furthermore, the outcome of the structural analysis of the two proteins upon binding of the inhibitors showed that the two proteins (SARS-CoV-2 Sgp and hACE-2) were stable, and the structural integrity of the proteins was not compromised. This study suggests pyrazolone-based compounds might be potent blockers of the viral entry into the host cells.

Recent Advances in Chalcone-Based Anticancer Heterocycles: A Structural and Molecular Target Perspective.

Chalcones are an interesting class of compounds endowed with a plethora of biological activities beneficial to human health. These chemotypes have continued to attract increased research attention over the years; hence, numerous natural and synthetic chalcones have found with interesting anticancer activities through the inhibition of various molecular targets including ABCG2, BCRP, P-glycoprotein, 5α-reductase, Androgen Receptor (AR), Histone Deacetylases (HDAC), Sirtuin 1, proteasome, Vascular Endothelial Growth Factor (VEGF), Cathepsin-K, tubulin, CDC25B phosphatase, Topoisomerase, EBV, NF-κB, mTOR, BRAF, and Wnt/ß-catenin. Moreover, the study of intrinsic mechanisms of action, particularly relating to specific cellular pathways and modes of engagement with molecular targets, may help medicinal chemists to develop more effective, selective, and cost-effective chalcone-based anticancer drugs. This review, therefore, sheds light on the effect of structural variations on the anticancer potency of chalcone hybrids reported in 2018-2019 alongside their mechanism of action, molecular targets, and potential impacts on effective cancer chemotherapy.

An appraisal of anti-mycobacterial activity with structure-activity relationship of piperazine and its analogues: A review.

Piperazine, is privileged six membered nitrogen containing heterocyclic ring also known as 1,4-Diazacyclohexane. Consequently, piperazine is a versatile medicinally important scaffold and is an essential core in numerous marketed drugs with diverse pharmacological activities. In recent years several potent molecules containing piperazine as an essential subunit of the structural frame have been reported, especially against Mycobacterium tuberculosis (MTB). Remarkably, a good number of these reported molecules also displayed potential activity against multidrug-resistant (MDR), and extremely drug-resistant (XDR) strains of MTB. In this review, we have made a concerted effort to retrace anti-mycobacterial compounds for the past five decades (1971-2019) specifically where piperazine has been used as a vital building block. This review will benefit medicinal chemists as it elaborates on the design, rationale and structure-activity relationship (SAR) of the reported potent piperazine based anti-TB molecules, which in turn will assist them in addressing the gaps, exploiting the reported strategies and developing safer, selective, and cost-effective anti-mycobacterial agents.

One-Pot, Multicomponent, Diastereoselective, Green Synthesis of 3,4-Dihydro-2H-benzo[b][1,4]oxazine Analogues.

A novel green and efficient catalyst-free, mild one-pot, multicomponent synthetic strategy has been developed to construct substituted 3,4-dihydro-2H-benzo[b][1,4]oxazine. This reaction proceeds via in situ formation of Schiff-base followed by base mediated alkylation with phenacyl bromide/substituted phenacyl bromide, finally leading to intramolecular cyclization to give a mixture of diastereomers with excellent diastereoselectivity (up to dr = 99:1), which were isolated as a single diastereomer in moderate to excellent yields (41-92%). Besides, this new versatile methodology provides a wide scope for the synthesis of different functionally substituted benzoxazine scaffolds and can be further exploited as building blocks for the synthesis of multifaceted molecular structures, especially for pharmaceutical applications.