Current Drug Targets - Volume 24, Issue 5, 2023

Bone morphogenetic proteins are a center of serious concern and are known to execute various cancer-related issues. The BMP signaling cascades have become more unpredictable as a result of their pleiotropic and risky characteristics, particularly when it comes to cancer responses. This perspective discusses the current therapeutic implications, emphasizes different cellular aspects that impact the failures of the current drug treatments, and speculates on future research avenues that include novel strategies like metabolomic studies and bio-mimetic peptide therapeutics to mitigate cancerous outcomes.

Humanity has been battling with tuberculosis (TB) for a long period, and despite the availability of drugs well-known to act against the deadly microbe, the menace is still very far from reaching its end. Moreover, problems related to TB chemotherapy, such as lengthy treatment periods leading to poor patient compliance, increasing drug resistance, and association with another deadlier disease HIV-AIDS, make the situation alarming, thereby pressing the need for the discovery of new potent drugs urgently. Therefore, a drug target that is essential for survival and exclusive to M. tuberculosis presents a promising platform to explore novel molecules against the microorganism for better pathogen clearance with minimal toxicity. The shikimate pathway that leads to the synthesis of essential aromatic amino acids is one such attractive target. Shikimate kinase, the fifth enzyme of this pathway, converts shikimate to shikimate-3-phosphate by using ATP as a cosubstrate. Targeting shikimate kinase could be an effective strategy in light of its essentiality and absence of any homologue in mammals. This review discusses different strategies adopted for discovering novel compounds or scaffolds targeting M. tuberculosis shikimate kinase (MtSK) in vitro. The application of substrate analogues, their structure, and ligand-based approach for screening a library of anti-mycobacterial compounds, marine-derived molecules, and commercially available libraries have yielded promising MtSK inhibitors exhibiting micro-molar activities. To develop these leads into future drugs with minimum off-target effects on the host microenvironment, the molecules need to be structurally optimized for improved activities against enzymes and whole-cell organisms.

More people are diagnosed with thyroid cancer than any other endocrine tumor. Differentiated thyroid cancer is often treated by removing the thyroid gland (thyroidectomy), iodizing radiation, or inhibiting thyroid stimulating hormone (TSH). Advanced thyroid carcinomas are notoriously resistant to chemotherapy, thus the pursuit of alternative treatments is vital. The best methods for treating individuals with advanced nonmedullary and medullary thyroid carcinomas are discussed in this post. Numerous tyrosine kinase inhibitors and antiangiogenic inhibitors, two types of novel target therapy, have shown promise in studies for individuals with thyroid cancer. Both the positive and unfavourable outcomes of clinical studies of these drugs were addressed. The findings presented here are encouraging, but more study is required to establish whether or not this method is effective in the treatment of thyroid cancer.

Background: Parasitic human infectious diseases are a worldwide health problem due to the increased resistance to conventional drugs. For this reason, the identification of novel molecular targets and the discovery of new chemotherapeutic agents are urgently required. Metalo- aminopeptidases are promising targets in parasitic infections. They participate in crucial processes for parasite growth and pathogenesis. Objective: In this review, we describe the structural, functional and kinetic properties, and inhibitors, of several parasite metalo-aminopeptidases, for their use as targets in parasitic diseases. Conclusion: Plasmodium falciparum M1 and M17 aminopeptidases are essential enzymes for parasite development, and M18 aminopeptidase could be involved in hemoglobin digestion and erythrocyte invasion and egression. Trypanosoma cruzi, T. brucei and Leishmania major acidic M17 aminopeptidases can play a nutritional role. T. brucei basic M17 aminopeptidase down-regulation delays the cytokinesis. The inhibition of Leishmania basic M17 aminopeptidase could affect parasite viability. L. donovani methionyl aminopeptidase inhibition prevents apoptosis but not the parasite death. Decrease in Acanthamoeba castellanii M17 aminopeptidase activity produces cell wall structural modifications and encystation inhibition. Inhibition of Babesia bovis growth is probably related to the inhibition of the parasite M17 aminopeptidase, probably involved in host hemoglobin degradation. Schistosoma mansoni M17 aminopeptidases inhibition may affect parasite development, since they could participate in hemoglobin degradation, surface membrane remodeling and eggs hatching. Toxoplasma gondii M17 aminopeptidase inhibition could attenuate parasite virulence, since it is apparently involved in the hydrolysis of cathepsin Cs- or proteasome-produced dipeptides and/or cell attachment/invasion processes. These data are relevant to validate these enzymes as targets.