Targeting Metalloenzymes: The “Achilles’ Heel” of Viruses and Parasites

Moianos, Dimitrios; Prifti, Georgia-Myrto; Makri, Maria; Zoidis, Grigoris

doi:10.3390/ph16060901

Cited by 9 publications

(5 citation statements)

References 158 publications

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“…13 C NMR (63 MHz, CDCl 3 ) δ 163.3 (dd, 1 J C-F = 252. 16 Hz, 3 J C-F = 11.7 Hz, ArC2,C6), 155.79 (ArC=O), 146.86 (NHC(=O)OtBu), 137.43 (t, 3 J C-F = 7.72 Hz, ArC4), 110.02 (dd, 2 J C-F = 25.75 Hz, 4 J C-F = 8.97 Hz, ArC3,C5), 109.34 (t, 2 J C-F = 25.53 Hz, ArC1), 80.24 (-OC(CH 3 ) 3 ), 47.84 (s, CH2NHBoc), 28.41 (-OC(CH 3 ) 3 ). Elemental analysis calcd (%) for C 13 H 15 F 2 NO 3 : C, 57.56; H, 5.57; N, 5.16; found: C, 57.74; H, 5.76; N, 5.01.…”

Section: Synthesis Of O-substituted Hydroxylamines 29-31mentioning

confidence: 99%

“…Once the (−) DNA strand has been synthesized inside the viral capsid, the RNase H domain cleaves the pgRNA template strand to expose the newly synthesized (−) DNA strand so it can template synthesis of the (+) DNA strand [ 14 , 15 ]. RNase H is a metalloenzyme and acts through a metal-chelation hydrolysis mechanism which requires two Mg 2+ ions coordinated by four carboxylic amino acid moieties (the “D-E-D-D” motif) in the enzyme‘s active site [ 16 ]. There is no crystal structure for HBV P or its RNase H domain, so our group generated and validated an HBV P folding model (including the RNase H catalytic domain) using AlphaFold [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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N-Hydroxypiridinedione: A Privileged Heterocycle for Targeting the HBV RNase H

Moianos,

Makri,

Prifti

et al. 2024

Molecules

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Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome replication. Inhibition of RNase H activity prevents (+) DNA strand synthesis and results in the accumulation of non-functional genomes, terminating the viral replication cycle. RNase H, though promising, remains an under-explored drug target against HBV. We previously reported the identification of a series of N-hydroxypyridinedione (HPD) imines that effectively inhibit the HBV RNase H. In our effort to further explore the HPD scaffold, we designed, synthesized, and evaluated 18 novel HPD oximes, as well as 4 structurally related minoxidil derivatives and 2 barbituric acid counterparts. The new analogs were docked on the RNase H active site and all proved able to coordinate the two Mg2+ ions in the catalytic site. All of the new HPDs effectively inhibited the viral replication in cell assays exhibiting EC50 values in the low μM range (1.1–7.7 μM) with low cytotoxicity, resulting in selectivity indexes (SI) of up to 92, one of the highest reported to date among HBV RNase H inhibitors. Our findings expand the structure–activity relationships on the HPD scaffold, facilitating the development of even more potent anti-HBV agents.

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Section: Synthesis Of O-substituted Hydroxylamines 29-31mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

N-Hydroxypiridinedione: A Privileged Heterocycle for Targeting the HBV RNase H

Moianos,

Makri,

Prifti

et al. 2024

Molecules

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“…Among potential drug targets against zoonotic infectious diseases, metalloproteins are involved in essential viral and parasitic functions. − In particular, metalloenzymes represent crucial targets in drug development due to their diverse roles in biological processes and disease pathways. These enzymes, which require metal ions for their catalytic activities, play pivotal roles in various cellular functions, such as DNA replication, signal transduction, and metabolism.…”

Section: Introductionmentioning

confidence: 99%

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma

Rossi,

Tudino,

Carullo

et al. 2024

ACS Infect. Dis.

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The term "zoonosis" denotes diseases transmissible among vertebrate animals and humans. These diseases constitute a significant public health challenge, comprising 61% of human pathogens and causing an estimated 2.7 million deaths annually. Zoonoses not only affect human health but also impact animal welfare and economic stability, particularly in low-and middleincome nations. Leishmaniasis and schistosomiasis are two important neglected tropical diseases with a high prevalence in tropical and subtropical areas, imposing significant burdens on affected regions. Schistosomiasis, particularly rampant in sub-Saharan Africa, lacks alternative treatments to praziquantel, prompting concerns regarding parasite resistance. Similarly, leishmaniasis poses challenges with unsatisfactory treatments, urging the development of novel therapeutic strategies. Effective prevention demands a One Health approach, integrating diverse disciplines to enhance diagnostics and develop safer drugs. Metalloenzymes, involved in parasite biology and critical in different biological pathways, emerged in the last few years as useful drug targets for the treatment of human diseases. Herein we have reviewed recent reports on the discovery of inhibitors of metalloenzymes associated with zoonotic diseases like histone deacetylases (HDACs), carbonic anhydrase (CA), arginase, and heme-dependent enzymes.

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“…Metalloenzymes are involved in various biological processes, including epigenetic regulation, immune regulation, antimicrobial resistance and metabolism. Therefore, metalloenzymes are associated with a variety of diseases such as cancer, arthritis, cardiovascular disease, glaucoma, Alzheimer’s and AIDS [ 1 , 2 ]. At least 558 out of the 1371 Enzyme Commission (EC) entries recorded in MACiE databases are attributed to metal-dependent enzymes, which represents a significant portion of the enzyme family [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Metalloenzyme Inhibitors Based on Property Characterization: Strategy and Application for HDAC1 Inhibitors

Zhang,

Yang,

Yang

et al. 2024

Molecules

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Metalloenzymes are ubiquitously present in the human body and are relevant to a variety of diseases. However, the development of metalloenzyme inhibitors is limited by low specificity and poor drug-likeness associated with metal-binding fragments (MBFs). A generalized drug discovery strategy was established, which is characterized by the property characterization of zinc-dependent metalloenzyme inhibitors (ZnMIs). Fifteen potential Zn2+-binding fragments (ZnBFs) were identified, and a customized pharmacophore feature was defined based on these ZnBFs. The customized feature was set as a required feature and applied to a search for novel inhibitors for histone deacetylase 1 (HDAC1). Ten potential HDAC1 inhibitors were recognized, and one of them (compound 9) was a known potent HDAC1 inhibitor. The results demonstrated the effectiveness of our strategy to identify novel inhibitors for zinc-dependent metalloenzymes.

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Targeting Metalloenzymes: The “Achilles’ Heel” of Viruses and Parasites

Cited by 9 publications

References 158 publications

N-Hydroxypiridinedione: A Privileged Heterocycle for Targeting the HBV RNase H

N-Hydroxypiridinedione: A Privileged Heterocycle for Targeting the HBV RNase H

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma

Discovery of Novel Metalloenzyme Inhibitors Based on Property Characterization: Strategy and Application for HDAC1 Inhibitors

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