γ-AApeptides as a New Class of Peptidomimetics: Design, Synthesis, and Applications.

Peptidomimetics are studied for medicinal application because of their ability to mimic hierarchical structures of peptides and proteins. To break the limitation and expand the peptidomimetics family, a new class of peptidomimetics based on peptide nucleic acids (PNAs) backbone - "γ-AApeptides" was developed. Compared with previous peptidomimetics, γ-AApeptides possess prominent advantages such as resistance to proteolytic degradation, enhanced chemodiversity, good selectivity and outstanding bioactivity. The synthesis of γ-AApeptides is carried out using a ''monomer building block'' strategy which is facile and efficient. γ-AApeptides are able to mimic primary and secondary structures of therapeutic peptides, which make them promising candidates for molecular probes and potential drug leads. In the past decade, several interesting structures and applications of γ-AApeptides have been developed by different approaches such as structure-based design, combinatorial library screening, and peptides selfassembly and folding. By following the mechanism of host-defense peptides (HDPs), antibiotic γ- AApeptides showed broad-spectrum activity. At the same time, γ-AApeptides can be used for combinatorial library screening because of their structural stability and their chemodiversity. Anticancer agents, anti-T2DM (Type 2 diabetes mellitus) agents, anti-HIV (human immuno-deficiency virus) agents and anti-Alzheimer's disease agents were developed by combinatorial screening and rational design. Furthermore, γ-AApeptides as biopolymers, nanomaterials, supramolecular structures and self-assembly architectures were studied due to their unique backbone structures. Therefore, γ-AApeptides may play an important role in the development of peptidomimetics.

An update on the emerging approaches for histone deacetylase (HDAC) inhibitor drug discovery and future perspectives.

INTRODUCTION: HDACs catalyze the removal of acetyl groups from the ε-N-acetylated lysine residues of various protein substrates including both histone and nonhistone proteins. Different HDACs have distinct biological functions and are recruited to specific regions of the genome. HDAC inhibitors have attracted much attention in recent decades; indeed, there have been more than thirty HDAC inhibitors investigated in clinic trials with five approvals being achieved. AREAS COVERED: This review covers the emerging approaches for HDAC inhibitor drug discovery from the past five years and includes discussion of structure-based rational design, isoform selectivity, and dual mechanism/multi-targeting. Chemical structures in addition to the in vitro and in vivo inhibiting activity of these compounds have also been discussed. EXPERT OPINION: The exact role and biological functions of HDACs is still under investigation with a variety of HDAC inhibitors having been designed and evaluated. HDAC inhibitors have shown promise in treating cancer, AD, metabolic disease, viral infection, and multiple sclerosis, but there is still a lot of room for clinical improvement. In the future, more efforts should be put into (i) HDAC isoform identification (ii) the optimization of selectivity, activity, and pharmacokinetics; and (iii) unconventional approaches for discovering different effective scaffolds and pharmacophores.

Recent Progress on the Discovery of NLRP3 Inhibitors and their Therapeutic Potential.

BACKGROUND: Inflammation is the body's immune system's fast coordinating response to irritants caused by pathogens, external injuries, and chemical or radiation effects. The nucleotidebinding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. The dysfunction of NLRP3 inflammasome contributes to various pathogeneses of complex diseases, such as uncontrolled infection, autoimmune diseases, neurodegenerative diseases, and metabolic disorders. This review describes recent progress on the discovery of NLRP3 inflammasome inhibitors and their therapeutic potential. METHODS: Based on the mechanism of NLRP3 activation, several types of NLRP3 inhibitors are described and summarized according to their origins, structures, bioactivity, and mechanism of action. Structure-Activity Relationship (SAR) is also listed for different scaffolds, as well as effective pharmacophore. RESULTS: Over one-hundred papers were included in the review. The development of NLRP3 inhibitors has been described from the earliest glyburide in 2001 to the latest progress in 2019. Several series of inhibitors have been categorized, such as JC-series based on glyburide and BC-series based on 2APB. Many other small molecules such as NLRP3 inhibitors are also listed. SAR, application in related therapeutic models, and five different action mechanisms are described. CONCLUSION: The findings of this review confirmed the importance of developing NLRP3 inflammasome inhibitors. Various NLRP3 inhibitors have been discovered as effective therapeutic treatments for multiple diseases, such as type II diabetes, experimental autoimmune encephalomyelitis, stressrelated mood disorders, etc. The development of a full range of NLRP3 inflammasome inhibitors is still at its foundational phase. We are looking forward to the identification of inhibitory agents that provide the most potent therapeutic strategies and efficiently treat NLRP3 inflammasome-related inflammatory diseases.

PSMA-targeted nanoparticles for specific penetration of blood-brain tumor barrier and combined therapy of brain metastases.

Breast cancer brain metastases (BCBM) represent a major cause of morbidity and mortality among patients with breast cancer. Systemic drug therapy, which is usually effective against peripheral breast cancers, is often ineffective on BCBM due to its poor penetration through the blood-brain tumor barrier (BTB). In this study, prostate-specific membrane antigen (PSMA) with internalization function was found to be specifically up-regulated on BCBM-associated BTB while barely detectable in normal blood-brain barrier (BBB). Here, a nanotechnology approach is reported that can overcome the BTB through ACUPA (A) and cyclic TT1 (cT) co-functionalized nanoparticles (A-NPs-cT). A-NPs-cT selectively target PSMA on BTB for specific BTB crossing and specially bind with p32 for BCBM targeting. We disclosed the effectual synergism of doxorubicin (DOX) and lapatinib (LAP) for BCBM combined therapy. A-NPs-cT exhibited boosted uptake than integrin-targeting RGD-modified NPs in BTB endothelial cells and displayed about 4.57-fold stronger penetration through the BCBM-associated BTB as compared to the normal BBB. In vivo studies showed specific BTB crossing, and remission of BCBM and prolonged survival with DOX and LAP combinatorial regimen. A-NPs-cT based DOX and LAP innovative combined therapy envisioned improved therapeutic intervention for clinical management of BCBM, for which surgery is generally inapplicable and insufficient.

The Activity of Small Urea-γ-AApeptides Toward Gram-Positive Bacteria.

Host Defense Peptides (HDPs) have gained considerable interest due to the omnipresent threat of bacterial infection as a serious public health concern. However, development of HDPs is impeded by several drawbacks, such as poor selectivity, susceptibility to proteolytic degradation, low-to-moderate activity and requiring complex syntheses. Herein we report a class of lipo-linear α/urea-γ-AApeptides with a hybrid backbone and low molecular weight. The heterogeneous backbone not only enhances chemodiversity, but also shows effective antimicrobial activity against Gram-positive bacteria and is capable of disrupting bacterial membranes and killing bacteria rapidly. Given their low molecular weight and ease of access via facile synthesis, they could be practical antibiotic agents.

Facilely accessible quinoline derivatives as potent antibacterial agents.

Quinoline compounds have been extensively explored as anti-malaria and anti-cancer agents for decades and show profound functional bioactivities, however, the studies of these compounds in other medicinal fields have lagged dramatically. In this study, we report the development of a series of facilely accessible quinoline derivatives that display potent antibacterial activity against a panel of multidrug-resistant Gram-positive bacterial strains, especially C. difficile. We also demonstrated that these molecules are effective in vivo against C. difficile. These results revealed that these types of quinoline compounds could serve as prototypes for the development of an appealing class of antibiotic agents used to combat Gram-positive drug-resistant bacterial strains, including C. difficile.

Small Antimicrobial Agents Based on Acylated Reduced Amide Scaffold.

Prevalence of drug-resistant bacteria has emerged to be one of the greatest threats in the 21st century. Herein, we report the development of a series of small molecular antibacterial agents that are based on the acylated reduced amide scaffold. These molecules display good potency against a panel of multidrug-resistant Gram-positive and Gram-negative bacterial strains. Meanwhile, they also effectively inhibit the biofilm formation. Mechanistic studies suggest that these compounds kill bacteria by compromising bacterial membranes, a mechanism analogous to that of host-defense peptides (HDPs). The mechanism is further supported by the fact that the lead compounds do not induce resistance in MRSA bacteria even after 14 passages. Lastly, we also demonstrate that these molecules have therapeutic potential by preventing inflammation caused by MRSA induced pneumonia in a rat model. This class of compounds could lead to an appealing class of antibiotic agents combating drug-resistant bacterial strains.

[Modified abdominal radical trachelectomy for treatment of cervical carcinomas].

OBJECTIVE: To investigate the possibility and effect of modified abdominal radical trachelectomy in treating women with early cervical cancers who desired to preserve fertility. METHODS: From October 2002 through September 2004, we performed abdominal radical trachelectomy with a modified Smith's style on 13 patients which were biopsy-proven early stage cervical carcinomas and had a desire to preserve fertility. Pelvic lymphadenectomies were performed in all patients. Radical trachelectomy was performed immediately if lymph nodes were negative. RESULTS: Thirteen women underwent this procedure. The average age was 29.4 years (range 21 - 35 years); 9 were null gravid and 4 were multipara. Mean operative time was 158 minutes (135 - 185 minutes), with a mean blood loss of 120 ml (100 - 180 ml), and an average hospital stay of 9.7 days. There was no intra- or post-operative complication. With an average follow-up of 21.3 months, there have been no recurrences. Five out of 13 patients have tried to get pregnant after operation, 3 patients conceived pregnancy, 1 patient was premature labor at 34 weeks, and the other 2 patients are pregnant at the moment. CONCLUSION: The modified abdominal radical trachelectomy which has less injury and fewer side-effects is safe and effective in treating patients with early cervical carcinoma, and can also give the patients chances to preserve their fertility in the future.