In contrast to the traditional mechanism of drug action that relies on the reversible, noncovalent interaction of a ligand with its biological target, a targeted covalent inhibitor (TCI) is designed such that the initial, reversible association is followed by the formation of a covalent bond between an electrophile on the ligand and a nucleophilic center in the protein. Although this approach offers a variety of potential benefits (high potency and extended duration of action), concerns over the possible toxicological consequences of protein haptenization have hindered the development of the TCI concept. Recently, approaches to mitigate the risk of serious adverse reactions to this new class of agent have emerged, thus stimulating interest in the field and leading to authorization of the first cadre of TCIs to be marketed. The covalent inhibitor approach is rapidly gaining acceptance as a valuable tool in drug discovery, and is poised to make a major impact on the design of enzyme inhibitors and receptor modulators.
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http://dx.doi.org/10.1002/anie.201601091 | DOI Listing |
Pharmaceutics
December 2024
Law Sau Fai Institute for Advancing Translational Medicine in Bone &Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China.
: Traditional paclitaxel therapy often results in significant side effects due to its non-specific targeting of cancer cells. Peptide aptamer-paclitaxel conjugates present a promising alternative by covalently attaching paclitaxel to a versatile peptide aptamer via a linker. Compared to antibody-paclitaxel conjugates, peptide aptamer-paclitaxel conjugates offer several advantages, including a smaller size, lower immunogenicity, improved tissue penetration, and easier engineering.
View Article and Find Full Text PDFPharmaceuticals (Basel)
January 2025
School of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
DPP4 is an enzyme with multiple natural substrates and probable involvement in various mechanisms. It constitutes a drug target for the treatment of diabetes II, although, also related to other disorders. While a number of drugs with competitive inhibitory action and covalent binding capacity are available, undesired side effects exist partly attributed to drug kinetics, and research for finding novel, potent, and safer compounds continues.
View Article and Find Full Text PDFPathogens
December 2024
Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China.
Due to the lack of agents that directly target covalently closed circular DNA and integrated HBV DNA in hepatocytes, achieving a complete cure for chronic hepatitis B (CHB) remains challenging. The latest guidelines recommend (hepatitis B surface antigen) HBsAg loss as the ideal treatment target for improving liver function, histopathology, and long-term prognosis. However, even after HBsAg loss, hepatitis B virus can persist, with a risk of recurrence, reactivation, cirrhosis, and hepatocellular carcinoma.
View Article and Find Full Text PDFMolecules
January 2025
MBC Pharma Inc., Aurora, CO 80045, USA.
Background: The use of the bone-seeking properties of bisphosphonates (BPs) to target the delivery of therapeutic drugs is a promising approach for the treatment of bone metastases. Currently, the most advanced example of this approach is a gemcitabine-ibandronate conjugate (GEM-IB), where the bone-targeting BP ibandronate (IB) is covalently linked to the antineoplastic agent gemcitabine (GEM) via a spacer phosphate group. In the present study, we describe the development of a new analytical platform to evaluate the metabolism and pharmacokinetics of GEM-IB in mice and dogs and the results of proof-of-concept studies assessing the pharmacokinetics of GEM-IB in dogs and mice.
View Article and Find Full Text PDFBiomolecules
January 2025
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Wytemaweg 80, 3015CN Rotterdam, The Netherlands.
Hepatitis B virus (HBV) is a major global health issue, with an estimated 254 million people living with chronic HBV infection worldwide as of 2022. Chronic HBV infection is the leading cause of cirrhosis and liver cancer. Current treatment with nucleos(t)ide analogs is effective in the suppression of viral activity but generally requires lifelong treatment.
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