Current Protein and Peptide Science - Volume 23, Issue 10, 2022

Tuberculosis (TB) is a highly contagious infection with extensive mortality and morbidity. The rise of TB-superbugs (drug-resistant strains) with the increase of their resistance to conventional antibiotics has prompted a further search for new anti-mycobacterial agents. It is difficult to breach the barriers around TB bacteria, including mycolic cell wall, granuloma, biofilm and mucus, by conventional antibiotics in a short span of time. Hence, there is an essential need for molecules with an unconventional mode of action and structure that can efficiently break the barriers around mycobacterium. Antimicrobial peptides (AMP) are essential components of innate immunity having cationic and amphipathic characteristics. Lines of evidence show that AMPs have good myco-bactericidal and antibiofilm activity against normal as well as antibiotic-resistant TB bacteria. These peptides have shown direct killing of bacteria by membrane lysis and indirect killing by activation of innate immune response in host cells by interacting with the component of the bacterial membrane and intracellular targets through diverse mechanisms. Despite a good anti-mycobacterial activity, some undesirable characteristics are also associated with AMP, including hemolysis, cytotoxicity, susceptibility to proteolysis and poor pharmacokinetic profile, and hence only a few clinical studies have been conducted with these biomolecules. The design of new combinatorial therapies, including AMPs and particulate drug delivery systems, could be new potential alternatives to conventional antibiotics to fight MDR- and XDRTB. This review outlined the array of AMP roles in TB therapy, possible mechanisms of actions, activities, and current advances in pragmatic strategies to improve challenges accompanying the delivery of AMP for tuberculosis therapeutics.

Mitochondria are important intracellular organelles because of their key roles in cellular metabolism, proliferation, and programmed cell death. The differences in the structure and function of the mitochondria of healthy and cancerous cells have made mitochondria an interesting target for drug delivery. Mitochondrial targeting is an emerging field as the targeted delivery of cytotoxic payloads and antioxidants to the mitochondrial DNA is capable of overcoming multidrug resistance. Mitochondrial targeting is preferred over nuclear targeting because it can take advantage of the distorted metabolism in cancer. The negative membrane potential of the inner and outer mitochondrial membranes, as well as their lipophilicity, are known to be the features that drive the entry of compatible targeting moiety, along with anticancer drug conjugates, towards mitochondria. The design of such drug nanocarrier conjugates is challenging because they need not only to target the specific tumor/cancer site but have to overcome multiple barriers as well, such as the cell membrane and mitochondrial membrane. This review focuses on the use of peptide-based nanocarriers (organic nanostructures such as liposomes, inorganic, carbon-based, and polymers) for mitochondrial targeting of the tumor/cancer. Both in vitro and in vivo key results are reported.

Nuclear factor erythroid 2 (NFE 2) - related factor 2 (NFE2L2 or NRF2) is one of the transcription factors predominantly related to the expression of antioxidant genes. NRF2 plays a pivotal role in controlling redox potential in several tumor characteristics, including cancer cell metabolism, stem-cell-like characteristics, tumor aggressiveness, invasion, and metastasis. Further, it was recently discovered that the noncanonical pathway of NRF2 activation was involved in carcinogenesis. Cancerrelated changes (e.g., metabolic flexibility) that support cancer progression were found to be redox and NRF2 dependent. The pro or antineoplastic effects of NRF2 are essentially based on the specific molecular characteristics of the type of cancer. Therefore, systematic investigation of NRF2 signaling is necessary to clarify its role in cancer etiology. Understanding the role of NRF2 in triggering gene expressions in different types of cancer is quite challenging, which might be useful to target those genes for better clinical outcomes. To decipher the role of NRF2 in tumor formation and progression, largescale genomic and transcriptomic studies are required to correlate the clinical outcomes with the activity of the NRF2 expression system. This review attempts to give insights into the understanding of the role of NRF2 in cancer.

As an important pectin enzyme, pectin methylesterase (PME) can hydrolyze methyl esters, release methanol and reduce esterification. It is essential in regulating pollen tube development, root extension, and fruit ripening. Pectin methylesterase inhibitors (PMEI) can specifically bind PME and inhibit its activity, which jointly determines the esterification degree of pectin. PMEI has important application prospects in plant pest control, fruits and vegetable processing fields. In this paper, the gene families, crystal structures, molecular recognition, and applications in plants and industry are reviewed for the PME and PMEI systems. Finally, the semi-rational design of PMEI is discussed and discussed prospected.

Background: Micropollutants comprise organic/mineral substances that cause an undesirable impact on the environment, by affecting life at all scales. In this study, we explored the changes they impart on the global proteome of a soil bacterium Serratia nematodiphila MB307, for two classes of pollutants, i.e., Azo dyes (Methyl orange, Congo red) and a pharmaceutical (Ibuprofen). Methods: The 100 μg pollutant supplemented alteration of pure S. nematodiphila MB307 culture after 24 hours of incubation at 37 °C and its control was analyzed using a differential proteomics approach. MaxQuant software with the Perseus package was used for data analysis purposes. Results: Prominently, ribosomal proteins and chaperones were up or downregulated in the whole cell and membranous fraction. Conclusion: This illustrates dynamic protein production adaptation of bacteria, to cope with stress and cell growth/division trade-off for survival. A collective pattern of survival under stress or pollution resistance could not be decrypted for all classes of pollutants, portraying dissimilar mechanisms of coping with differently structured pollutant moieties.

Background: Mimusops elengi, popularly known as Bakula in Ayurvedic Medicine, is a member of the Sapotaceae family. Concerning the traditional and Ayurvedic medicinal use of Mimusops elengi leaves, especially in wound healing and oral care, the plausible presence of proteolytic activity in an aqueous Mimusops elengi leaf extract was investigated in our study. Methods: Mimusops elengi Gelatinolytic Protease was named after fractioning the extract. The Zymogram assay validated the gelatin specificity. The effect of MEGP on the wound healing process was investigated using a different assay. Results: The presence of protease with gelatinolytic & caseinolytic activity at 62.53±1.43 U/h and 15.31±0.64 U/h, respectively. The aqueous enzyme fraction was named Mimusops elengi Gelatinolytic Protease (MEGP). The specificity of gelatin was confirmed by zymogram. Gelatinolytic activity of MEGP was also higher than that of trypsin at 27.96±0.38 U/h. MEGP was 49.14±1.61 % inhibited by PMSF, indicating the predominant presence of serine proteases. The optimal pH and temperature for MEGP were found to be 8 and 37°C, implying that it is an alkaline protease. MEGP dissolved the blood clot at a rate of 8.41±1.04 U/h, which is higher than the trypsin clot-dissolving rate of 1.027±0.04 U/h. The plasma clot hydrolytic capacity is confirmed when MEGP hydrolyzes alpha-polymer subunits in a dose-dependent manner. Conclusion: This investigation shows that MEGP has a plasmin-like activity that possesses a significant role in clot disintegration and other wound ailments, warranting its use in traditional Indian medicine.