Medicinal Chemistry Spotlight
Medicinal Chemistry is a broad field at the intersection of chemistry and medicine. It involves the search for new compounds that can alleviate or cure human diseases. With so many known diseases, it is difficult to cover all of the excellent work being done by medicinal chemists around the world. In this issue we offer a peek at recent breakthroughs that hold promise of improved therapies.
Scientists develop sustainable alternative to shark-derived vaccine ingredient
Squalene is a key vaccine ingredient sourced from sharks, used to boost immune responses in adjuvants. It has been widely used in COVID-19 vaccines and in candidate vaccines for Tuberculosis and Malaria. However, the overfishing of sharks for this purpose is putting several shark species at risk. The global shark and ray population has fallen by 71% since 1970.
The team used ß-farnesene derived from yeast fermentation and converted it into 20 different analogues of squalene through chemical synthesis.
The new squalene-like compounds were tested in blood assays to check immune responses. The researchers also formulated into an inactivated flu vaccine and tested the immune response of mice. At least four of the molecules showed enhanced adjuvant activity compared to shark squalene.
Vaccines must be approved with their adjuvants, to establish protective efficacy and safety. Before the new compounds can be introduced, more preclinical work in different animal models is needed.
Furthermore, sharks’ marine environment is heavily polluted with PCBs and heavy metals. Researchers say this is another reason for the pharmaceutical industry to seek alternatives to shark squalene.
Protein degraders can break cancer progression
Researchers at the University of Michigan Rogel Cancer Center are hopeful that protein degraders can open new targets for the fight against cancer. The researchers have identified a protein degrader (AK-2292) specific to a protein called STAT5, that can effectively degrade it within a cell.
In recent years, new bivalent protein degraders intentionally designed for targeted protein degradation (TPD) have advanced to clinical trials. Most of these clinical candidates are designed for oral use, which presents some therapeutic constraints for drug delivery. Typically, oral drugs have to withstand the digestive system to reach the blood stream.
Protein degraders have attracted attention as useful tools for basic research and therapeutic applications. They can achieve selective protein knockdown in a reversible and tunable manner, without the need for genetic modification.
Protein degraders are compounds that can selectively target and degrade specific proteins inside cells. They are made up of three components: an E3 ubiquitin ligase ligand, a linker, and a ligand for a target protein of interest. The E3 ubiquitin ligase ligand binds to an E3 ligase enzyme, which is responsible for tagging proteins with ubiquitin, a process that targets them for degradation by the 26S proteasome. The ligand for the target protein binds to the protein of interest, bringing it in proximity to the E3 ligase. The linker connects these two ligands. This allows the formation of a ternary complex in which the E3 ligase is "hijacked" to ubiquitinate and degrade the target protein.
STAT5 is a key protein that helps in the progression of some types of cancers. Earlier attempts to remove it were problematic as there was no drug that could inhibit it without other STAT proteins. The protein-breaker approach has solved a major challenge for STAT5 targeting. The team was able to remove the protein from human chronic myeloid leukemia cell lines. Their results have shown tumor regression when these cell lines were introduced in mice.
The team at Rogel Cancer Center has already been working on different protein breakers, some of them in advanced pre-clinical stages. While they are hopeful to start clinical trials of these drugs, this process usually takes time.
Cromolyn derivatives: potential candidates for Alzheimer’s disease
The pathology of Alzheimer's Disease (AD) has been associated with the misfolding of amyloid-beta (Aβ) and tau proteins, as well as neuroinflammatory signaling. Numerous drug candidates are being investigated to reduce AD symptoms.
Chromolyn is a compound originally discovered from khella (Ammi visnaga). Its sodium salt is a known bronchodilator for asthma treatment. It is effective in inhibiting the release of inflammatory mediators, such as histamine and leukotrienes released by mast cells.
Researchers have been looking for ways to use Chromolyn for other conditions. A recent study on chromolyn derivatives led by a team of Korean and American researchers aimed to identify the anti-AD effects of two chemical derivatives modified from cromoglicic acid, CNU 010 and CNU 011. The inhibitory effects of Aβ and tau were determined by the thioflavin T assay. The researchers performed western blots to confirm the effects on inflammation. The study found that CNU 010 and CNU 011 significantly inhibited the aggregation of Aβ and tau proteins and reduced the expression levels of early and late inflammatory signaling markers.
These results suggest that CNU 010 and CNU 011 have potential as drug candidates for AD treatment due to their multiple beneficial effects against abnormal protein aggregation and neuroinflammatory signaling.
For further reading, explore latest articles in some of the leading oncology journals from Bentham Science:
Also read our Anti-Inflammatory Medicine Article Collection..
New books on medicinal chemistry from Bentham Science:
Advanced Pharmaceutical and Herbal Nanoscience for Targeted Drug Delivery Systems Part I
Advanced Pharmaceutical and Herbal Nanoscience for Targeted Drug Delivery Systems Part II
Alkaloids and Other Nitrogen-Containing Derivatives
Flavonoids and Phenolics