Drug repurposing: An effective strategy to accelerate contemporary drug discovery

Zhan, Peng; Ouyang, Liang

doi:10.1016/j.drudis.2022.05.026

Cited by 29 publications

(20 citation statements)

References 26 publications

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“…Hence, the application of repurposed approved drugs has received widespread attention in recent decades because it lowers barriers to the clinical application of drugs. 5 The underlying mechanisms of alkali burn-induced corneal damage are complicated and still need to be elucidated. It has been generally accepted that oxidative stress, activated proinflammatory cytokines, and NV play vital roles in pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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A simple but novel glycymicelle ophthalmic solution based on two approved drugs empagliflozin and glycyrrhizin: in vitro/in vivo experimental evaluation for the treatment of corneal alkali burns

Zong-jian

Zhang

Wei³

et al. 2023

Biomater. Sci.

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Section: Introductionmentioning

confidence: 99%

“…Hence, the application of repurposed approved drugs has received widespread attention in recent decades because it lowers barriers to the clinical application of drugs. 5…”

Section: Introductionmentioning

confidence: 99%

A simple but novel glycymicelle ophthalmic solution based on two approved drugs empagliflozin and glycyrrhizin: in vitro/in vivo experimental evaluation for the treatment of corneal alkali burns

Zong-jian

Zhang

Wei³

et al. 2023

Biomater. Sci.

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“…9,10 Therefore, there is an urgent need to develop antifungals to combat fungal infection and overcome escalating issues of drug resistance in fungi. 8 The discovery of novel antifungals has been difficult, 11 as the fungal efflux system enables indiscriminate expulsion of endogenous and exogenous toxins for self-protection. 12 Some efflux substrates, 13 known as expelled potential active agents (EPAAs), may exhibit antifungal activity when they accumulate in fungal cells.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The discovery of novel antifungals has been difficult, as the fungal efflux system enables indiscriminate expulsion of endogenous and exogenous toxins for self-protection . Some efflux substrates, known as expelled potential active agents (EPAAs), may exhibit antifungal activity when they accumulate in fungal cells.…”

Section: Introductionmentioning

confidence: 99%

Benzamidine Conjugation Converts Expelled Potential Active Agents into Antifungals against Drug-Resistant Fungi

Wang,

Jin,

Xie

et al. 2023

J. Med. Chem.

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Fungal infections present a growing global public health concern, necessitating the development of novel antifungal drugs. However, many potential antifungals, particularly the expelled potential active agents (EPAAs), are often underestimated owing to their limitations in cellular entry or expulsion by efflux pumps. Herein, we identified 68 EPAAs out of 2322 candidates with activity against a Candida albicans efflux pump-deficient strain and no inhibitory activity against the wild-type strain. Using a novel conjugation strategy involving benzamidine (BM) as a mitochondrion-targeting warhead, we successfully converted EPAAs into potent antifungals against various urgent-threat azole-resistantCandida strains. Among the obtained EPAA-BM conjugates, IS-2-BM (11) exhibited excellent antifungal activities and induced negligible drug resistance. Furthermore, IS-2-BM prevented biofilm formation, eradicated mature biofilms, and exhibited excellent therapeutic effects in a murine model of systemic candidiasis. These findings provide a promising strategy for increasing the possibilities of discovering more antifungals.

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“…Drug repurposing, i.e., the use of existing drugs for a different therapeutic application, is a common strategy presenting potential advantages, such as decreased costs and minimized risks during drug development. 36 In the complicated field of antibiotics, numerous active substances have been considered, and one of the most promising classes is represented by biomolecules belonging to the nucleoside analogue (NA) class. 37 NAs are indeed a major therapeutic class, mainly known as antiviral and anticancer agents.…”

mentioning

confidence: 99%

Zidovudine-β-Lactam Pronucleoside Strategy for Selective Delivery into Gram-Negative Bacteria Triggered by β-Lactamases

Rosales-Hurtado,

Sannio,

Lari

et al. 2023

ACS Infect. Dis.

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Addressing antibacterial resistance is a major concern of the modern world. The development of new approaches to meet this deadly threat is a critical priority. In this article, we investigate a new approach to negate bacterial resistance: exploit the β-lactam bond cleavage by β-lactamases to selectively trigger antibacterial prodrugs into the bacterial periplasm. Indeed, multidrug-resistant Gram-negative pathogens commonly produce several β-lactamases that are able to inactivate β-lactam antibiotics, our most reliable and widely used therapeutic option. The chemical structure of these prodrugs is based on a monobactam promoiety, covalently attached to the active antibacterial substance, zidovudine (AZT). We describe the synthesis of 10 prodrug analogues (5a−h) in four to nine steps and their biological activity. Selective enzymatic activation by a panel of β-lactamases is demonstrated, and subsequent structure−activity relationships are discussed. The best compounds are further evaluated for their activity on both laboratory strains and clinical isolates, preliminary stability, and toxicity.

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Drug repurposing: An effective strategy to accelerate contemporary drug discovery

Cited by 29 publications

References 26 publications

A simple but novel glycymicelle ophthalmic solution based on two approved drugs empagliflozin and glycyrrhizin: in vitro/in vivo experimental evaluation for the treatment of corneal alkali burns

A simple but novel glycymicelle ophthalmic solution based on two approved drugs empagliflozin and glycyrrhizin: in vitro/in vivo experimental evaluation for the treatment of corneal alkali burns

Benzamidine Conjugation Converts Expelled Potential Active Agents into Antifungals against Drug-Resistant Fungi

Zidovudine-β-Lactam Pronucleoside Strategy for Selective Delivery into Gram-Negative Bacteria Triggered by β-Lactamases

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