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The rise of drug resistance presents a significant challenge in the treatment of infectious diseases. This Review summarizes the status and mechanisms of drug resistance in malaria, human immunodeficiency virus (HIV) infection and tuberculosis, and explores strategies to address resistance that could be incorporated into drug development across these disease areas.
RNA has revolutionized modern medicine, creating great expectations. However, challenges with this class of drugs persist. In this Review, John Androsavich analyses lessons learnt from RNA modalities such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNA), and discusses strategies to develop RNA drug platforms, improving their applicability, efficacy and safety profiles.
Immunogenic cell death (ICD) is crucial for the elicitation of anticancer immune responses by therapy, but the successful development of ICD-inducing treatments is hindered by various obstacles. This Review provides an overview of the core mechanisms of ICD, discusses obstacles to the development of novel ICD modulators and assesses established and innovative therapeutic approaches for ICD induction.
Since the groundbreaking discovery of RNAi more than 25 years ago, several small interfering RNA (siRNA)-based therapies that target the liver have gained approval. This Review discusses principal considerations in siRNA-based drug development, focusing on the medicinal chemistry of siRNA design, the application of informatics, delivery platforms and future directions.
The development of prodrugs — derivatives of active pharmaceutical ingredients (APIs) with little or no biological activity themselves that are converted into the API after administration — can address issues with properties of the API such as poor bioavailability. This article provides a holistic analysis of approved prodrugs and discusses trends in prodrug design, their indications, mechanisms of API release and the chemistry of promoieties added to APIs to form prodrugs.
Bispecific antibodies (bsAbs) can mediate therapeutic effects beyond those of natural monospecific antibodies. This Review provides an overview of recent developments in the field of bsAbs for cancer therapy and an outlook into next-generation bsAbs in earlier stages of development.
Treatments for tuberculosis have markedly improved in recent years, but lung disease caused by nontuberculous mycobacteria (NTM) is on the rise and lacks effective cures. This Review discusses promising small-molecule drug candidates and innovative clinical trial designs and highlights how lessons from tuberculosis therapeutic development can be applied to NTM disease.
Significant progress has been made in understanding the influence of membrane transporters in drug disposition and response. Here, the International Transporter Consortium provides an update on the current status of membrane transporters in drug development and regulatory requirements, discusses recent scientific advances in the field and highlights future directions and unanswered questions.
The field of nucleic acid therapeutics is rapidly expanding, with mRNA drug and vaccine candidates now under development for diverse indications. However, various safety concerns are associated with the mRNA platform. This Review discusses key challenges and toxicities identified during the development of mRNA drugs and vaccines, assesses models and tools used to limit toxicity, highlighting knowledge gaps and future directions.
This Review discusses the mechanisms that regulate stabilization of hypoxia-inducible factors (HIFs), and the pharmacological strategies to activate or inhibit HIFs in diseases such as ischaemia, inflammation, cancer, retinal neovascularization and pulmonary hypertension.
The TAM tyrosine kinase receptors TYRO3, AXL and MERTK regulate tissue and immune homeostasis. This Review discusses how their aberrant signalling is linked to diseases such as cancer, fibrosis and viral infection, and surveys the therapeutic landscape of TAM receptor inhibitors in preclinical and clinical development.
A diverse range of systems have recently been developed to promote the degradation of extracellular and membrane protein targets by using bispecific antibodies, conjugates or small molecules to traffic targeted proteins to the lysosome. This article describes and categorizes systems for extracellular targeted protein degradation, including LYTACs, ATACs, AbTACs, PROTABs and KineTACs, and discusses their advantages and the challenges ahead to realizing their therapeutic potential.
The potential of harnessing tRNAs to treat genetic diseases has recently gained significant attention. Here, Coller and Ignatova provide an overview of the history and potential applications of tRNA-based therapies, summarize advances in tRNA cargo design and delivery strategies, and assess the challenges encountered in establishing tRNAs as effective and safe therapeutics.
Inflammasomes are central instigators of the inflammatory response to infection and tissue damage and key regulators in diverse diseases. Here, the authors describe signalling mechanisms that regulate the NLRP3 inflammasome pathways and recent progress in the development of inhibitors and agonists that are advancing into the clinic.
The recent success of mRNA vaccines has boosted the prospects for the development of a new class of designer medicines based on mRNA. This Review discusses the multiple design parameters that need to be carefully considered to create highly effective mRNA medicines.
Synapses are crucial nodes for communication between neurons and are frequently damaged or dysfunctional in a range of neurodegenerative diseases. In their Review, Dejanovic, Sheng and Hanson outline the current understanding of pathological mechanisms operating at the synapse. They discuss several synapse-targeted approaches in preclinical and clinical development, which could be particularly valuable in combination with other therapeutic strategies.
This Review discusses current research strategies to overcome resistance to CAR-T cell therapy in blood cancers, including optimization of CAR design, improvement of T cell function and persistence, modulation of the immunosuppressive tumour microenvironment and synergistic combination strategies.
T cell receptors (TCRs) enable the targeting of proteins selectively expressed by cancer cells, including neoantigens, cancer germline antigens and viral oncoproteins. This Review discusses the current cancer treatment landscape using TCRs and TCR-like molecules, including adoptive cell transfer of T cells expressing endogenous or engineered TCRs or TCR bispecific engagers.
New classes of antibiotic with activity against Gram-negative bacteria that are resistant to existing drugs are urgently needed, but have been very challenging to identify. This Review describes promising but as-yet-unrealized targets for antibacterial drugs against Gram-negative bacteria and highlights lessons learned from past drug discovery programmes.
CRISPR-based genome editing has the potential to treat many human genetic diseases, but achieving stable, efficient and safe in vivo delivery remains a challenge. This Review assesses current delivery systems for genome editors—focusing on adeno-associated viruses and lipid nanoparticles—and highlights data from recent clinical trials. Emerging delivery systems and ongoing challenges in the field are discussed.