Current status and trends in small nucleic acid drug development:Leading the future

Small nucleic acid drugs,composed of nucleotides,represent a novel class of pharmaceuticals that differ significantly from conventional small molecule and antibody-based therapeutics.These agents function by selectively targeting specific genes or their corresponding messenger RNAs(mRNAs),further modulating gene expression and regulating translation-related processes.Prominent examples within this category include antisense oligonucleotides(ASO),small interfering RNAs(siRNAs),micro-RNAs(miRNAs),and aptamers.The emergence of small nucleic acid drugs as a focal point in contemporary biopharmaceutical research is attributed to their remarkable specificity,facile design,abbreviated development cycles,expansive target spectrum,and prolonged activity.Overcoming challenges such as poor stability,immunogenicity,and permeability issues have been addressed through the integration of chemical modifications and the development of drug delivery systems.This review provides an overview of the current status and prospective trends in small nucleic acid drug development.Commencing with a historical context,we introduce the primary classifications and mechanisms of small nucleic acid drugs.Subsequently,we delve into the advantages of the U.S.Food and Drug Administration(FDA)approved drugs and mainly discuss the challenges encountered during their development.Apart from researching chemical modification and delivery system that efficiently deliver and enrich small nucleic acid drugs to target tissues,promoting endosomal escape is a critical scientific question and important research direction in siRNA drug development.Future directions in this field will prioritize addressing these challenges to facilitate the clinical transformation of small nucleic acid drugs.

Peptide-drug conjugates(PDCs):a novel trend of research and development on targeted therapy,hype or hope?

Peptide-drug conjugates(PDCs)are the next generation of targeted therapeutics drug after antibody-drug conjugates(ADCs),with the core benefits of enhanced cellular permeability and improved drug selectivity.Two drugs are now approved for market by US Food and Drug Administration(FDA),and in the last two years,the pharmaceutical companies have been developing PDCs as targeted therapeutic candidates for cancer,coronavirus disease 2019(COVID-19),metabolic diseases,and so on.The therapeutic benefits of PDCs are significant,but poor stability,low bioactivity,long research and development time,and slow clinical development process as therapeutic agents of PDC,how can we design PDCs more effectively and what is the future direction of PDCs?This review summarises the components and functions of PDCs for therapeutic,from drug target screening and PDC design improvement strategies to clinical applications to improve the permeability,targeting,and stability of the various components of PDCs.This holds great promise for the future of PDCs,such as bicyclic peptide-toxin coupling or supramolecular nanostructures for peptide-conjugated drugs.The mode of drug delivery is determined according to the PDC design and current clinical trials are summarised.The way is shown for future PDC development.