Design methods for antimicrobial peptides with improved performance

The recalcitrance of pathogens to traditional antibiotics has made treating and eradicating bacterial infections more difficult.In this regard,developing new antimicrobial agents to combat antibiotic-resistant strains has become a top priority.Antimicrobial peptides(AMPs),a ubiquitous class of naturally occurring compounds with broadspectrum antipathogenic activity,hold significant promise as an effective solution to the current antimicrobial resistance(AMR)crisis.Several AMPs have been identified and evaluated for their therapeutic application,with many already in the drug development pipeline.Their distinct properties,such as high target specificity,potency,and ability to bypass microbial resistance mechanisms,make AMPs a promising alternative to traditional antibiotics.Nonetheless,several challenges,such as high toxicity,lability to proteolytic degradation,low stability,poor pharmacokinetics,and high production costs,continue to hamper their clinical applicability.Therefore,recent research has focused on optimizing the properties of AMPs to improve their performance.By understanding the physicochemical properties of AMPs that correspond to their activity,such as amphipathicity,hydrophobicity,structural conformation,amino acid distribution,and composition,researchers can design AMPs with desired and improved performance.In this review,we highlight some of the key strategies used to optimize the performance of AMPs,including rational design and de novo synthesis.We also discuss the growing role of predictive computational tools,utilizing artificial intelligence and machine learning,in the design and synthesis of highly efficacious lead drug candidates.

Bioactive peptides from scorpion venoms:therapeutic scaffolds and pharmacological tools

Evolution and natural selection have endowed animal venoms,including scorpion venoms,with a wide range of pharmacological properties.Consequently,scorpions,their venoms,and/or their body parts have been used since time immemorial in traditional medicines,especially in Africa and Asia.With respect to their pharmacological potential,bioactive peptides from scorpion venoms have become an important source of scientific research.With the rapid increase in the characterization of various components from scorpion venoms,a large number of peptides are identified with an aim of combating a myriad of emerging global health problems.Moreover,some scorpion venom-derived peptides have been established as potential scaffolds helpful for drug development.In this review,we summarize the promising scorpion venoms-derived peptides as drug candidates.Accordingly,we highlight the data and knowledge needed for continuous characterization and development of additional natural peptides from scorpion venoms,as potential drugs that can treat related diseases.

Anticarin-β shows a promising antiosteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis

Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex(TRiC) contains eight paralogous subunits(CCT1-8), and assists the folding of as many as 10% of cytosolic proteome.TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma,and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.