This review summarizes recent developments in using bioorthogonal chemistry in prodrug design for the delivery of traditional small molecule- and gasotransmitter-based therapeutics.
Carbon monoxide is an intrinsic signaling molecule with importance on par with that of nitric oxide. During the past decade, pharmacological studies have amply demonstrated the therapeutic potential of carbon monoxide. However, such studies were mostly based on CO inhalation and metal-based CO releasing molecules (CO-RMs). The field is now at the stage that a major effort is needed to develop pharmaceutically acceptable forms of CO for delivery via various routes such as oral, injection, infusion, or topical applications. This review examines the state of the art, discusses existing hurdles to overcome, and proposes developmental strategies necessary to address remaining drug delivery issues.
Direct-acting antiviral agents (DAAs) represent a class of drugs targeting viral proteins and have been demonstrated to be very successful in combating viral infections in clinic. However, DAAs suffer from several inherent limitations, including narrow-spectrum antiviral profiles and liability to drug resistance, and hence there are still unmet needs in the treatment of viral infections. In comparison, host targeting antivirals (HTAs) target host factors for antiviral treatment. Since host proteins are probably broadly required for various viral infections, HTAs are not only perceived, but also demonstrated to exhibit broad-spectrum antiviral activities. In addition, host proteins are not under the genetic control of viral genome, and hence HTAs possess much higher genetic barrier to drug resistance as compared with DAAs. In recent years, much progress has been made to the development of HTAs with the approval of chemokine receptor type 5 antagonist maraviroc for human immunodeficiency virus treatment and more in the pipeline for other viral infections. In this review, we summarize various host proteins as antiviral targets from a medicinal chemistry prospective. Challenges and issues associated with HTAs are also discussed. K E Y W O R D S broad-spectrum antivirals, direct-acting antiviral agents, drug resistance, host targeting antiviral agents
Hedgehog (Hh) signaling is an essential pathway in the human body, and plays a major role in embryo development and tissue patterning. Constitutive activation of the Hh signaling pathway through sporadic mutations or other mechanisms is explicitly associated with cancer development and progression in various solid malignancies. Therefore, targeted inhibition of the Hh signaling pathway has emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Vismodegib, a first-in-class Hh signaling pathway inhibitor was approved by the US Food and Drug Administration in 2012, and sonidegib, another potent Hh pathway inhibitor, received FDA's approval in 2015 as a new treatment of locally advanced or metastatic basal cell carcinoma. The clinical success of vismodegib and sonidegib provided strong support for the development of Hh signaling pathway inhibitors via targeting the smoothened (Smo) receptor. Moreover, Hh signaling pathway inhibitors aimed to target proteins, which are downstream or upstream of Smo, have also been pursued based on the identification of additional therapeutic benefits. Recently, much progress has been made in Hh singling and inhibitors of this pathway. Herein, medicinal chemistry strategies, especially the structural optimization process of different classes of Hh inhibitors, are comprehensively summarized. Further therapeutic potentials and challenges are also discussed.
Carbon monoxide prodrugs with triggered release profiles are highly desirable for targeted CO delivery to minimize their untoward side-effects. Herein, we describe a series of pH-sensitive metal-free CO prodrugs which are stable under acidic conditions and yet begin to release CO in response to increases in pH with tunable and predictable release rates.
Sulfur dioxide (SO2) is being recognized as a possible endogenous gasotransmitter with importance on par with that of NO, CO, and H2S. Herein we describe a series of SO2 prodrugs that are activated for SO2 release via a bioorthogonal click reaction. The release rate can be tuned by adjusting the substituents on the prodrug.
Although a myriad of bioorthogonal
prodrugs have been developed,
very few of them present both fast reaction kinetics and complete
cleavage. Herein, we report a new bioorthogonal prodrug strategy with
both fast reaction kinetics (k
2: ∼103 M–1 s–1) and complete
cleavage (>90% within minutes) using the bioorthogonal reaction
pair
of N-oxide and boron reagent. Distinctively, an innovative
1,6-elimination-based self-immolative linker is masked by N-oxide, which can be bioorthogonally demasked by a boron
reagent for the release of both amino and hydroxy-containing payload
in live cells. Such a strategy was applied to prepare a bioorthogonal
prodrug for a camptothecin derivative, SN-38, resulting in 10-fold
weakened cytotoxicity against A549 cells, 300-fold enhanced water
solubility, and “on-demand” activation upon a click
reaction both in vitro and in vivo. This novel bioorthogonal prodrug strategy presents significant
advances over the existing ones and may find wide applications in
drug delivery in the future.
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