Vol 31, No 20 (2024)

Proteins have been playing a critical role in the regulation of diverse biological processes related to human life. With the increasing demand, functional proteins are sparse in this immense sequence space. Therefore, protein design has become an important task in various fields, including medicine, food, energy, materials, etc. Directed evolution has recently led to significant achievements. Molecular modification of proteins through directed evolution technology has significantly advanced the fields of enzyme engineering, metabolic engineering, medicine, and beyond. However, it is impossible to identify desirable sequences from a large number of synthetic sequences alone. As a result, computational methods, including data-driven machine learning and physics-based molecular modeling, have been introduced to protein engineering to produce more functional proteins. This review focuses on recent advances in computational protein design, highlighting the applicability of different approaches as well as their limitations.

Introduction:Chronic myeloid leukemia (CML) is a kind of malignant tumor formed by the clonal proliferation of bone marrow hematopoietic stem cells. BCR-ABL fusion protein, found in more than 90% of patients, is a vital target for discovering anti- CML drugs. Up to date, imatinib is the first BCR-ABL tyrosine kinase inhibitor (TKI) approved by the FDA for treating CML. However, the drug resistance problems appeared for many reasons, especially the T135I mutation, a \"gatekeeper\" of BCR-ABL. Currently, there is no long-term effective and low side effect drug in clinical.

Methods:This study intends to find novel TKIs targeting BCR-ABL with high inhibitory activity against T315I mutant protein by combining artificial intelligence technology and cell growth curve, cytotoxicity, flow cytometry and Western blot experiments.

Results:The obtained compound was found to kill leukemia cells, which had good inhibitory efficacy in BaF3/T315I cells. Compound no 4 could induce cell cycle arrest, cause autophagy and apoptosis, and inhibit the phosphorylation of BCR-ABL tyrosine kinase, STAT5 and Crkl proteins.

Conclusion:The results indicated that the screened compound could be used as a lead compound for further research to discover ideal chronic myeloid leukemia therapeutic drugs.

TYK2 (tyrosine-protein kinase 2) is a non-receptor protein kinase belonging to the JAK family and is closely associated with various diseases, such as psoriasis, inflammatory bowel disease, systemic lupus erythematosus. TYK2 activates the downstream proteins STAT1-5 by participating in the signal transduction of immune factors such as IL-12, IL-23, and IL-10, resulting in immune expression. The activity of the inhibitor TYK2 can effectively block the transduction of excessive immune signals and treat diseases. TYK2 inhibitors are divided into two types of inhibitors according to the different binding sites. One is a TYK2 inhibitor that binds to JH2 and inhibits its activity through an allosteric mechanism. The representative inhibitor is BMS-986165, developed by Bristol-Myers Squibb. The other class binds to the JH1 adenosine triphosphate (ATP) site and prevents the catalytic activity of the kinase by blocking ATP and downstream phosphorylation. This paper mainly introduces the protein structure, signaling pathway, synthesis, structure-activity relationship and clinical research of TYK2 inhibitors.

Neuroglobin (Ngb) is an oxygen-binding globin protein that is mainly expressed in the neurons of the central and peripheral nervous system. However, moderate levels of Ngb have also been detected in non-neural tissues. Ngb and Ngb modulating factors have been increasingly studied over the last decade due to their neuroprotective role in neurological disorders and hypoxia. Studies have shown that a number of chemicals, pharmaceuticals, and herbal compounds can modulate the expression of Ngb at different dose levels, indicating a protective role against neurodegenerative diseases. Iron chelators, hormones, antidiabetic drugs, anticoagulants, antidepressants, plant derivatives and short-chain fatty acids are among these compounds. Therefore, this study aimed to review the literature focused on the possible effects and mechanisms of chemical, pharmaceutical, and herbal compounds on Ngbs.

Autophagy is a significant catabolic procedure that increases in stressful conditions. This mechanism is mostly triggered after damage to the organelles, the presence of unnatural proteins, and nutrient recycling in reaction to these stresses. One of the key points in this article is that cleaning and preserving damaged organelles and accumulated molecules through autophagy in normal cells helps prevent cancer. Since dysfunction of autophagy is associated with various diseases, including cancer, it has a dual function in tumor suppression and expansion. It has newly become clear that the regulation of autophagy can be used for the treatment of breast cancer, which has a promising effect of increasing the efficiency of anticancer treatment in a tissue- and cell-type-specific manner by affecting the fundamental molecular mechanisms. Regulation of autophagy and its function in tumorigenesis is a vital part of modern anticancer techniques. This study discusses the current advances related to the mechanisms that describe essential modulators of autophagy involved in the metastasis of cancers and the development of new breast cancer treatments.

Background and Aim:Mucopolysaccharidosis type III (MPS III) is a rare autosomal recessive lysosomal storage disease (LSD) caused by a deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs), mainly in the central nervous system. Trehalose has been proposed as a potential therapeutic agent to attenuate neuropathology in MPS III. We conducted a single- arm, open-label study to evaluate the efficacy of trehalose treatment in patients with MPS IIIA and MPS IIIB.

Methods:Five patients with MPS III were enrolled. Trehalose was administrated intravenously (15 g/week) for 12 weeks. Health-related quality of life and cognitive function, serum biomarkers, liver, spleen, and lung imaging were assessed to evaluate trehalose efficacy at baseline and trial end (week 12).

Results:TNO-AZL Preschool children Quality of Life (TAPQOL) scores increased in all patients, and the mean scores for quality of life were increased after the intervention. Serum GAG levels were reduced in all treated patients (however, the differences were not statistically significant). Alanine aminotransferase (ALT) levels were reduced in all patients post-treatment (p=0.0039). The mean levels of aspartate transaminase (AST) were also decreased after 12 weeks of treatment with Trehalose. Decreased serum pro-oxidant-antioxidant balance and increased GPX activity were observed at the end of the study. Decreases in mean splenic length were observed, whereas the liver volume did not change.

Conclusion:Improvements in health-related quality of life and serum biomarkers (GAGs, liver aminotransferase levels, antioxidant status), as well as liver and spleen size, were found following 3 months of trehalose administration in patients with MPS IIIA and MPS IIIB.