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Dr. Alessio Nocentini

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Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 50019 Florence, Italy
Interests: drug design; organic chemistry; molecular modelling; enzymology; metalloenzymes; carbonic anhydrases; GPCR; enzyme modulators; anticancer; antiinfectives; anti-inflammatory; anti-Alzheimer; multi-target directed ligands; spectroscopic studies; structure-based design; molecular dynamics
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Special Issue Information

Dear Colleagues,

Single-target drugs generally fail to achieve an adequate therapeutic outcome when used to treat multifactorial diseases. Drug combination therapies simultaneously modulating multiple targets demonstrated an enhanced therapeutic efficacy for the treatment of complex disorders, including tumors and neurodegenerative diseases. As a natural evolution of combined therapies, the interest in multi-target-directed ligands (MTDLs) has recently spread in the medicinal chemistry field. An MTDL acts as a unique molecular entity capable of concomitantly modulating the activity of more biological targets implicated in a disease. As such, MTLDs show improved pharmacokinetics, reaching the target tissue/organ as a single molecular entity, avoiding drug–drug interactions, and producing an overall greater synergistic effect compared to the simultaneous administration of multiple drugs. MTDLs may thus require lower doses, potentially reducing side effects and overcoming tolerance to single drugs. In this Special Issue, the Editors would like to encourage researchers investigating different research fields to submit their original or review articles with a focus on MTDLs and related design approaches, which have been studied to date in the treatment of diseases such as cancer, hyperlipidemia, HIV, hypertension, cardiovascular disease, pain, inflammation depression, infectious and neurodegenerative diseases, among others.

Dr. Alessio Nocentini
Guest Editor

Manuscript Submission Information

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Keywords

multi-target-directed ligands
drug discovery
drug design
synthesis
biological activity
polypharmacology
molecular modelling
cancer
neurodegenerative diseases
inflammation

Published Papers (2 papers)

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Research

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13 pages, 2304 KiB

Open AccessArticle

The Interactive Complex between Cytomegalovirus Kinase vCDK/pUL97 and Host Factors CDK7–Cyclin H Determines Individual Patterns of Transcription in Infected Cells

by Martin Schütz, Arne Cordsmeier, Christina Wangen, Anselm H. C. Horn, Emanuel Wyler, Armin Ensser, Heinrich Sticht and Manfred Marschall

Int. J. Mol. Sci. 2023, 24(24), 17421; https://doi.org/10.3390/ijms242417421 - 13 Dec 2023

Cited by 1 | Viewed by 754

Abstract

The infection of human cytomegalovirus (HCMV) is strongly determined by the host–cell interaction in a way that the efficiency of HCMV lytic replication is dependent on the regulatory interplay between viral and cellular proteins. In particular, the activities of protein kinases, such as cyclin-dependent kinases (CDKs) and the viral CDK ortholog (vCDK/pUL97), play an important role in both viral reproduction and virus–host interaction. Very recently, we reported on the complexes formed between vCDK/pUL97, human cyclin H, and CDK7. Major hallmarks of this interplay are the interaction between cyclin H and vCDK/pUL97, which is consistently detectable across various conditions and host cell types of infection, the decrease or increase in pUL97 kinase activity resulting from cyclin H knock-down or elevated levels, respectively, and significant trans-stimulation of human CDK7 activity by pUL97 in vitro. Due to the fact that even a ternary complex of vCDK/pUL97–cyclin H–CDK7 can be detected by coimmunoprecipitation and visualized by bioinformatic structural modeling, we postulated a putative impact of the respective kinase activities on the patterns of transcription in HCMV-infected cells. Here, we undertook a first vCDK/pUL97-specific transcriptomic analysis, which combined conditions of fully lytic HCMV replication with those under specific vCDK/pUL97 or CDK7 drug-mediated inhibition or transient cyclin H knockout. The novel results were further strengthened using bioinformatic modeling of the involved multi-protein complexes. Our data underline the importance of these kinase activities for the C-terminal domain (CTD) phosphorylation-driven activation of host RNA polymerase in HCMV-infected cells. The impact of the individual experimental conditions on differentially expressed gene profiles is described in detail and discussed. Full article

(This article belongs to the Special Issue Recent Advances on Multi-Target Directed Ligands)

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Review

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24 pages, 6492 KiB

Open AccessReview

‘Getting Better’—Is It a Feasible Strategy of Broad Pan-Antiherpesviral Drug Targeting by Using the Nuclear Egress-Directed Mechanism?

by Julia Tillmanns, Jintawee Kicuntod, Josephine Lösing and Manfred Marschall

Int. J. Mol. Sci. 2024, 25(5), 2823; https://doi.org/10.3390/ijms25052823 - 29 Feb 2024

Viewed by 640

Abstract

The herpesviral nuclear egress represents an essential step of viral replication efficiency in host cells, as it defines the nucleocytoplasmic release of viral capsids. Due to the size limitation of the nuclear pores, viral nuclear capsids are unable to traverse the nuclear envelope without a destabilization of this natural host-specific barrier. To this end, herpesviruses evolved the regulatory nuclear egress complex (NEC), composed of a heterodimer unit of two conserved viral NEC proteins (core NEC) and a large-size extension of this complex including various viral and cellular NEC-associated proteins (multicomponent NEC). Notably, the NEC harbors the pronounced ability to oligomerize (core NEC hexamers and lattices), to multimerize into higher-order complexes, and, ultimately, to closely interact with the migrating nuclear capsids. Moreover, most, if not all, of these NEC proteins comprise regulatory modifications by phosphorylation, so that the responsible kinases, and additional enzymatic activities, are part of the multicomponent NEC. This sophisticated basis of NEC-specific structural and functional interactions offers a variety of different modes of antiviral interference by pharmacological or nonconventional inhibitors. Since the multifaceted combination of NEC activities represents a highly conserved key regulatory stage of herpesviral replication, it may provide a unique opportunity towards a broad, pan-antiherpesviral mechanism of drug targeting. This review presents an update on chances, challenges, and current achievements in the development of NEC-directed antiherpesviral strategies. Full article

(This article belongs to the Special Issue Recent Advances on Multi-Target Directed Ligands)

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