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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
An alternative strategy known as PROTAC (proteolysis targeting chimeras) has been developed and is also described below. PROTAC is based on the design of a bifunctional complex that utilizes the ubiquitin-protease system to selectively degrade the transcription factor of interest, thus inhibiting the transcription process. One advantage of this approach is that it does not require a high concentration of the bifunctional complex to produce a therapeutic effect. Thus, PROTAC has become a promising strategy for treating a number of diseases including cancer.
Nanotechnology and Delivery System for Bioactive Antibiofilm Dental Materials
Published in Mary Anne S. Melo, Designing Bioactive Polymeric Materials for Restorative Dentistry, 2020
Jin Xiao, Yuan Liu, Marlise I. Klein, Anna Nikikova, Yanfang Ren
Recently, some new molecules are designed for efficient intraoral delivery of antimicrobials to prevent and treat the periodontal infection. The salivary statherin fragment, which has a high affinity for the tooth surfaces, was used as a carrier peptide. This was linked through the side chain of the N-terminal residue to the C-terminus of a defensive-like 12-residue peptide to generate two bifunctional hybrid molecules: one with an ester linkage, and the other with an anhydride bond between the carrier and the antimicrobial components. The bifunctional hybrid molecules could adhere to the tooth and pellicle surfaces uniformly and inhibit microbial accumulation. In addition, these bifunctional molecules would decrease the limitations and discomfort associated with the currently available local drug-delivery devices (Raj et al. 2008).
Immunoglobulins
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Genetic engineering has created additional types of antibodies which may have important clinical applications in the future. Bifunctional antibodies are created by the union of two different specificities in a single antibody molecule. That is, the divalent four chain unit is made up of two different heavy-light chain pairs, each with its own specificity. Such antibodies are made by fusing two hybridomas, creating hybrid-hybridomas. Such molecules may be used in a variety of ways to enhance immune effector mechanisms. For example, specificity for a cytotoxic T cell receptor may be linked with specificity for a viral, parasitic, or tumor antigen. The bifunctional antibody enhances cytotoxic activity.
Strategies for targeting undruggable targets
Published in Expert Opinion on Drug Discovery, 2022
Gong Zhang, Juan Zhang, Yuting Gao, Yangfeng Li, Yizhou Li
Recently, noteworthy development to deal with KRAS has been made via the introduction of bifunctional molecules. Researchers designed different forms of KRAS PROTAC molecules by linking the KRASG12C covalent-targeting moiety with the E3 ligase recruiting moiety. Gray and coworkers conjugated ARS-1620 with thalidomide to realize the degradation of over-expressed GFP-KRASG12C, but this conjugate failed to degrade endogenous KRASG12C [102]. Similarly, Crews and coworkers attached MRTX849 to VHL ligand, and the resulting molecule proved successful to degrade endogenous KRASG12C protein[103]. This again indicated the importance to choose the E3 ligase-recruiting molecule and to fine-tune the linker length in developing PROTACs. Furthermore, a bifunctional KRAS macromolecule degrader was developed by linking RAS-binding intrabody to E3 ligase domain (Ubox or VHL)[104]. This method resembles a kind of protein-based PROTACs. Besides bifunctional degraders, Shokat and coworkers linked ARS-1620 with immunophilin ligand (FK506 or cyclosporin A) to generate a bifunctional recruiter/stabilizer dragging KRAS in association with the immunophilin protein (FKBP12 or CypA), which in proof-of-concept blocked KRAS effector region with steric hinderance, enlightening a novel avenue to targeting undruggable proteins like KRAS[105].
Advances in mRNA-based drug discovery in cancer immunotherapy
Published in Expert Opinion on Drug Discovery, 2022
Claudia Augusta Di Trani, Myriam Fernandez-Sendin, Assunta Cirella, Aina Segués, Irene Olivera, Elixabet Bolaños, Ignacio Melero, Pedro Berraondo
Tumor-infiltrating cytotoxic T lymphocytes display a dampened antitumoral activity due to the influence of a hostile tumor environment characterized by the presence of immunosuppressive elements [58]. Over the years, researchers have sought to modulate the TME, either through reactivation of immune cells or neutralizing the immunosuppressive environment. Interestingly, synergistic effects can be achieved when both such strategies are combined. Recombinant bifunctional molecules such as immunocytokines or bispecific antibodies can exert this dual activity, but their large-scale production can be challenging. In vivo production of these complex molecules can be achieved by mRNA-encoded constructs. Van der Jeught et al. evaluated Fβ2 [59], a new mRNA-encoded fusokine composed of interferon beta (IFN-β) and the ectodomain of the TGF-β receptor II. This fusokine has a dual role: (i) it increases immune reactivity by potentiating the antigen-presenting function of dendritic cells while (ii) decreasing TGF-β mediated immunosuppression. Treating E.G7-OVA or TC-1-bearing mice with three intratumoral injections in a three-day interval resulted in increased long-term survival. This effect is mediated by CD8+ T cells since their depletion abrogated the observed therapeutic effect. Further, combining Fβ2 with anti-PD-1 monoclonal antibody delayed tumor growth.
Employing in vitro metabolism to guide design of F-labelled PET probes of novel α-synuclein binding bifunctional compounds
Published in Xenobiotica, 2021
Chukwunonso K. Nwabufo, Omozojie P. Aigbogun, Kevin J.H Allen, Madeline N. Owens, Jeremy S. Lee, Christopher P. Phenix, Ed S. Krol
Phase 1 metabolic studies utilizing hepatic microsomes in vitro are a typical first step in understanding drug metabolism. An advantage of using microsomes as an in vitro drug metabolism model is the ability to focus on generating sufficient amounts of presumptive P450-mediated phase I metabolites without contribution from other competing systems such as phase II metabolism and transporter-mediated processes (Temporal et al. 2017). It is our goal to use hepatic microsomes to determine whether our bifunctional compounds undergo Phase 1 metabolism and to identify those metabolic products. Several animal models of Parkinson’s disease exist so we have decided to carry out our assessment of in vitro metabolism using liver microsomes from several animals (mouse and rat) as well as human liver microsomes. An additional benefit to determining the metabolic stability of our bifunctional compounds is that knowledge of the regiochemistry of metabolic reactions can potentially inform less metabolically labile positions for incorporation of fluorine in our PET probe bifunctional analogues.