Bioorganic & Medicinal Chemistry最新文献

Methamphetamine (METH) substance use disorder is a long-standing and ever-growing public health concern. Efforts to develop successful immunotherapies are ongoing with vaccines that generate strong antibody responses are an area of significant research interest. Herein, we describe the development of a METH Hapten conjugate vaccine comprised of either two short-length peptides as linkers and mannan as an immunogenic delivery carrier. Initially, Hapten 1 (with a monoamine linker) and Hapten 2 (with a diamine linker) were synthesised. Each step of the Hapten synthesis were characterized by LC-MS and purified by Flash Chromatography and the identity of the purified Haptens were confirmed by ¹H NMR. Haptens were conjugated with mannan (a polymannose), and conjugation efficiency was confirmed by LC-MS, TLC, ¹H NMR, and 2,4 DNPH tests. The immunogenic potential of the two conjugated vaccines were assessed in mice with a 3-dose regimen. Concentrations of anti-METH antibodies were measured by enzyme-linked immunosorbent assay. All the analytical techniques confirmed the identity of Hapten 1 and 2 during the synthetic phase. Similarly, all the analytical approaches confirmed the conjugation between the Haptens and mannan. Mouse immunogenicity studies confirmed that both vaccine candidates were immunogenic and the vaccine with the monoamine linker plus adjuvants induced the highest antibody response after the second booster.

Since transition-metal-catalyzed reactions are one of the most powerful and direct approaches for the synthesis of organic molecules, translating them to biological systems for biomedical applications is an emerging field. The manipulation of transition metal reactions in biological settings for uncaging prodrugs and synthesizing bioactive drugs has been widely studied. To expand the toolbox of transition-metal-mediated prodrug strategy, this work introduces the 2′-alkynl-biphenylamine precursors for the synthesis of phenanthridine derivatives using a water-compatible gold-catalyzed hydroamination under mild conditions. Moreover, the structure–reactivity relationship revealed that the nucleophilicity of the amine group in the precursor was critical for facilitating the gold-catalyzed synthesis of phenanthridine derivatives. The research shows the potential to be used for phenanthridine-based prodrug designs in an aqueous solution.

Amyloid beta peptide (Aβ) and hyperphosphorylated neuronal tau proteins accumulate in neurofibrillary tangles in Alzheimer’s disease (AD), a chronic neurodegenerative illness. Chronic inflammation in the brain, which promotes disease progression, is another feature of the Alzheimer’s disease pathogenesis. Approximately 60–70 % of dementia cases are caused by AD. The development of effective therapies for the treatment of AD is urgently needed given the severity of the condition and its rapidly rising prevalence. Cholinesterase inhibitors, beta-amyloid (A-beta), tau inhibitors, and many other medications are currently used as preventive medicine for AD. These medications can temporarily suppress dementia symptoms but cannot halt or reverse the disease’s progression. Many international pharmaceutical companies have tried numerous times to develop an amyloid clearing medication based on the amyloid hypothesis, but without success. Therefore, the amyloid theory may not be entirely plausible. This review mainly covers the recent and important reported pharmacophores as the starting point to discuss already known targets like tau, butyrylcholinesterase, amyloid beta, and acetylcholinesterase and covers the literature between years 2019–2024.

Long non-coding RNAs (lncRNAs) represent the most diverse class of RNAs in cells and play crucial roles in maintaining cellular functions. RNA modifications, being a significant factor in regulating RNA biology, have been found to be extensively present in lncRNAs and exert regulatory effects on their behavior and biological functions. Most common types of RNA modifications in lncRNAs include N6-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), and N1-methyladenosine (m¹A). In this review, we summarize the major RNA modification types associated with lncRNAs, the regulatory roles of each modification, and the implications of modified lncRNAs in tumorigenesis and development. By examining these aspects, we aim to provide insights into the role of RNA modifications in lncRNAs and their potential impact on cancer biology.

Osteoporosis is a condition of progressive bone loss attributable to excessive osteoclastic activity. Acacetin is a potential candidate for osteoporosis therapy because it specifically suppressing osteoclastic function. However, the application of acacetin was limited by its poor solubility and bad pharmacokinetic behavior. In current work, we examined whether PEGylation of acacetin enhances its anti-osteoporosis activity in ovariectomy-induced osteoporosis and LPS-induced osteolysis. In the current study, three types of PEGylated acacetin (PEG₃-A, PEG₄-A, PEG₅-A) were tested for their effects on the solubility and anti-inflammatory activity of acacetin in vitro. PEG₅-Acacetin was selected for further investigation as it demonstrated the strongest anti-inflammatory activity comparable to that of naked acacetin and other two PEGylated acacetin. PEGylation in PEG₅-Acacetin increased maximum plasma concentration of acacetin by 620.77% in mice. Furthermore, PEG₅-A showed a higher anti-osteoclastogenic capacity in vitro than that of naked acacetin. It was found that PEG₅-A treatment in vivo mitigated lipopolysaccharide (LPS)- and ovariectomy (OVX)-induced bone loss in mice. More importantly, the in vivo efficiency of PEG₅-Acacetin was significantly better than that of naked acacetin. In summary, PEGylated acacetin possesses a clean advantage over the naked acacetin and would be a potential candidate for the osteoporosis therapy.

The unique and complex structure of papain-like protease (PL^pro) of the SARS-CoV-2 virus represents a difficult challenge for antiviral development, yet it offers a compelling validated target for effective therapy of COVID-19. The surge in scientific interest in inhibiting this cysteine protease emerged after its demonstrated connection to the cytokine storm in patients with COVID-19 disease. Furthermore, the development of new inhibitors against PL^pro may also be beneficial for the treatment of respiratory infections caused by emerging coronavirus variants of concern.

This review article provides a comprehensive overview of PL^pro inhibitors, focusing on the structural framework of the known inhibitor GRL0617 and its analogs. We categorize PL^pro inhibitors on the basis of their structures and binding site: Glu167 containing site, BL2 groove, Val70^Ub site, and Cys111 containing catalytic site. We summarize and evaluate the majority of GRL0617-like inhibitors synthesized so far, highlighting their published biochemical parameters, which reflect their efficacy. Published research has shown that strategic modifications to GRL0617, such as decorating the naphthalene ring, extending the aromatic amino group or the orthomethyl group, can substantially decrease the IC₅₀ from micromolar up to nanomolar concentration range. Some advantageous modifications significantly enhance inhibitory activity, paving the way for the development of new potent compounds. Our review places special emphasis on structures that involve direct modifications to the GRL0617 scaffold, including piperidine carboxamides and modified benzylmethylnaphthylethanamines (Jun9 scaffold). All these compounds are believed to inhibit the proteolytic, deubiquitination, and deISGylation activity of PL^pro, biochemical processes linked to the severe progression of COVID-19.

Finally, we summarize the development efforts for SARS-CoV-2 PL^pro inhibitors, in detailed structure–activity relationships diagrams. This aims to inform and inspire future research in the search for potent antiviral agents against PL^pro of current and emerging coronavirus threats.

Affibody molecules are 58-amino-acid peptides with a molecular weight of about 6.5 kDa, derived from the Z domain of Staphylococcal Protein A. Since they have been used as substitutes for antibodies in biomedicine, several therapeutic affibody molecules have been developed for clinical use. Additionally, affibody molecules have been designed for a range of different applications. This review focuses on the progress made in the last five years in the field of affibody molecules and their potential uses in medical imaging, especially in oncology and cancer treatment. It covers areas such as molecular imaging, targeted delivery of toxic drugs, and their use in combination with nanoparticles. We also highlight some current biomedical applications where affibody molecules are commonly used as a “guide.” Due to their many advantages, affibody molecules offer significant potential for applications in both biochemical and medical fields.