Novel peptidyl α-aminoalkylphosphonates as inhibitors of hepatitis C virus NS3/4A protease

Skoreński, Marcin; Pachota, Magdalena; Pyrć, Krzysztof; Sieńczyk, Marcin; Oleksyszyn, Józef

doi:10.1016/j.antiviral.2017.06.020

Cited by 6 publications

(7 citation statements)

References 45 publications

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“…Its inhibition has proven effective in reducing viral loads in humans [43]. Furthermore, several phosphonate derivatives were reported as potential inhibitors of HCV NS3 protease [44][45][46][47]. Meanwhile, HIV reverse transcriptase (RT) is an interesting target for the treatment of HIV disease.…”

Section: Resultsmentioning

confidence: 99%

Efficient one-pot, three-component procedure to prepare new α-aminophosphonate and phosphonic acid acyclic nucleosides

Baddi

Ouzebla

Mansouri

et al. 2020

Nucleosides, Nucleotides & Nucleic Acids

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Efficient one-pot, three components procedure to prepare new αamino phosphonate and phosphonic acid acyclic nucleosides An efficient one-pot three-component Kabachnick-Fields reaction of aldehydes (acyclic nucleosides), amines (or amino acid), and triethylphosphite proceeded for the synthesis of amino phosphonates using natural phosphate coated with iodine (I 2 @NP) as a catalyst. The novel α-aminophosphonate and phosphonic acid acyclic nucleosides were tested for their anti-HCV and anti-HIV activities.The molecular docking showed that the non-activity of these compounds may be is due to the absence of hydrophobic pharmacophores.

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Section: Resultsmentioning

confidence: 99%

Efficient one-pot, three-component procedure to prepare new α-aminophosphonate and phosphonic acid acyclic nucleosides

Baddi

Ouzebla

Mansouri

et al. 2020

Nucleosides, Nucleotides & Nucleic Acids

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“…It is known that α-aminophosphonic acids act directly and exclusively toward serine protease lacking reactivity with cysteine and aspartyl residue . The highly stable and irreversible complex with NS3 protease of phosphonic inhibitors was demonstrated a few years back with derivatives able to retain 95% of the activity for 40 h, in contrast to telaprevir-NS3 and boceprevir-NS3 complexes which had half-life values of 4 and 23 h, respectively . Extensive SAR exploration on the benzyl group of the precursor phosphinic acid 41 was conducted by insertion of different electron-withdrawing and electron-donating groups at the benzyl phosphinic moiety to evaluate the role of acid p K a in Caco-2 permeability.…”

Section: Hcv Ns3 Pis: Development Of Inhibitors Of First Second and T...mentioning

confidence: 99%

“…134 The highly stable and irreversible complex with NS3 protease of phosphonic inhibitors was demonstrated a few years back with derivatives able to retain 95% of the activity for 40 h, in contrast to telaprevir-NS3 and boceprevir-NS3 complexes which had half-life values of 4 and 23 h, respectively. 135 Extensive SAR exploration on the benzyl group of the precursor phosphinic acid 41 was conducted by insertion of different electron-withdrawing and electrondonating groups at the benzyl phosphinic moiety to evaluate the role of acid pK a in Caco-2 permeability. Overall, substitution with fluorine, methoxy, and methyl groups was well tolerated, with a preference for ortho-disubstitution probably due to the potential "shielding effect" on the polar phosphinic acid group.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Hepatitis C: The Story of a Long Journey through First, Second, and Third Generation NS3/4A Peptidomimetic Inhibitors. What Did We Learn?

Martino,

Petri,

De Rosa

2024

J. Med. Chem.

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Hepatitis C viral (HCV) infection is the leading cause of liver failure and still represents a global health burden. Over the past decade, great advancements made HCV curable, and sustained viral remission significantly improved to more than 98%. Historical treatment with pegylated interferon alpha and ribavirin has been displaced by combinations of direct-acting antivirals. These regimens include drugs targeting different stages of the HCV life cycle. However, the emergence of viral resistance remains a big concern. The design of peptidomimetic inhibitors (PIs) able to fit and fill the conserved substrate envelope region within the active site helped avoid contact with the vulnerable sites of the most common resistance-associated substitutions Arg155, Ala156, and Asp168. Herein, we give an overview of HCV NS3 PIs discovered during the past decade, and we deeply discuss the rationale behind the structural optimization efforts essential to achieve pangenotypic activity.

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“…For example, inhibition of the bifunctional activity (serine protease and NTPase/RNA helicase) of hepatitis C virus nonstructural protein 3, which is fundamental for viral polyprotein processing, RNA replication virion formation and blocking innate immune pathways [30], was recognized as an effective antiviral therapy [31]. Following this assumption Skoreński et al constructed a potent irreversible phosphonate inhibitor of two genotypes and four mutants of NS3/4A protease (Table 1, Entry 5 ) [24]. The most active structures contained, crucial for their potency, constrained bicyclic proline analogs, utilized previously to develop approved drugs Boceprevir (VICTRELIS™) [32] and Telaprevir (INCIVEK/INCIVIO™) [33].…”

Section: Inhibition Of Serine Proteasesmentioning

confidence: 99%

Recent Developments in Peptidyl Diaryl Phoshonates as Inhibitors and Activity-Based Probes for Serine Proteases

Maślanka

Mucha

2019

Pharmaceuticals

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This review presents current achievements in peptidyl diaryl phosphonates as covalent, specific mechanism-based inhibitors of serine proteases. Along three decades diaryl phosphonates have emerged as invaluable tools in fundamental and applicative studies involving these hydrolases. Such an impact has been promoted by advantageous features that characterize the phosphonate compounds and their use. First, the synthesis is versatile and allows comprehensive structural modification and diversification. Accordingly, reactivity and specificity of these bioactive molecules can be easily controlled by appropriate adjustments of the side chains and the leaving groups. Secondly, the phosphonates target exclusively serine proteases and leave other oxygen and sulfur nucleophiles intact. Synthetic accessibility, lack of toxicity, and promising pharmacokinetic properties make them good drug candidates. In consequence, the utility of peptidyl diaryl phosphonates continuously increases and involves novel enzymatic targets and innovative aspects of application. For example, conjugation of the structures of specific inhibitors with reporter groups has become a convenient approach to construct activity-based molecular probes capable of monitoring location and distribution of serine proteases.

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Novel peptidyl α-aminoalkylphosphonates as inhibitors of hepatitis C virus NS3/4A protease

Cited by 6 publications

References 45 publications

Efficient one-pot, three-component procedure to prepare new α-aminophosphonate and phosphonic acid acyclic nucleosides

Efficient one-pot, three-component procedure to prepare new α-aminophosphonate and phosphonic acid acyclic nucleosides

Hepatitis C: The Story of a Long Journey through First, Second, and Third Generation NS3/4A Peptidomimetic Inhibitors. What Did We Learn?

Recent Developments in Peptidyl Diaryl Phoshonates as Inhibitors and Activity-Based Probes for Serine Proteases

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