HIV-1 proteins join the family of LIM kinase partners. New roads open up for HIV-1 treatment

Manetti, Fabrizio

doi:10.1016/j.drudis.2011.08.004

Cited by 15 publications

(8 citation statements)

References 56 publications

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“…Finally, LIMK inhibitors could be potential therapeutic agents as a deregulation of LIMK activity has been reported in several diseases including cancers and cancer cell migration/invasion [8, 29, 66–68], Alzheimer's disease [69], schizophrenia [70], neurofibromatosis type 2 [53], psoriatic epidermal lesions [71], primary pulmonary hypertension [72], allergic diseases [73], ocular hyper-tension and glaucoma [74, 75], erectile dysfunction [76], HIV and other viral infections [77, 78]. …”

Section: Pharmacological Inhibitors Of Limk: Unique Tools For Deciphementioning

confidence: 99%

LIM kinases: cofilin and beyond

et al. 2017

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LIM kinases are common downstream effectors of several signalization pathways and function as a signaling node that controls cytoskeleton dynamics through the phosphorylation of the cofilin family proteins. These last 10 years, several reports indicate that the functions of LIM kinases are more extended than initially described and, specifically, that LIM kinases also control microtubule dynamics, independently of their regulation of actin microfilament. In this review we analyze the data supporting these conclusions and the possible mechanisms that could be involved in the control of microtubules by LIM kinases. The demonstration that LIM kinases also control microtubule dynamics has pointed to new therapeutic opportunities. Consistently, several new LIM kinase inhibitors have been recently developed. We provide a comprehensive comparison of these inhibitors, of their chemical structure, their specificity, their cellular effects as well as their effects in animal models of various diseases including cancer.

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Section: Pharmacological Inhibitors Of Limk: Unique Tools For Deciphementioning

confidence: 99%

LIM kinases: cofilin and beyond

et al. 2017

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“…Nevertheless, LIMK1-null mice and human adults with WS do not have the severe multiple developmental disorders normally seen in other developmental genetic diseases, suggesting that blocking LIMK1 is not fatal and that short-term or localized LIMK inhibition is likely tolerable in adults. Therefore, LIMK is considered a valuable target for treating various human diseases, such as metastatic cancer, Alzheimer's disease, and drug addiction (63–65). These previous studies are also consistent with our results showing that the LIMK inhibitors are generally nontoxic in our cell-based assays and in mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel Small-Molecule Inhibitors of LIM Domain Kinase for Inhibiting HIV-1

Guo

Dabbagh

et al. 2017

J Virol

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A dynamic actin cytoskeleton is necessary for viral entry, intracellular migration, and virion release. For HIV-1 infection, during entry, the virus triggers early actin activity by hijacking chemokine coreceptor signaling, which activates a host dependency factor, cofilin, and its kinase, the LIM domain kinase (LIMK). Although knockdown of human LIM domain kinase 1 (LIMK1) with short hairpin RNA (shRNA) inhibits HIV infection, no specific small-molecule inhibitor of LIMK has been available. Here, we describe the design and discovery of novel classes of small-molecule inhibitors of LIMK for inhibiting HIV infection. We identified R10015 as a lead compound that blocks LIMK activity by binding to the ATP-binding pocket. R10015 specifically blocks viral DNA synthesis, nuclear migration, and virion release. In addition, R10015 inhibits multiple viruses, including Zaire ebolavirus (EBOV), Rift Valley fever virus (RVFV), Venezuelan equine encephalitis virus (VEEV), and herpes simplex virus 1 (HSV-1), suggesting that LIMK inhibitors could be developed as a new class of broad-spectrum antiviral drugs.IMPORTANCE The actin cytoskeleton is a structure that gives the cell shape and the ability to migrate. Viruses frequently rely on actin dynamics for entry and intracellular migration. In cells, actin dynamics are regulated by kinases, such as the LIM domain kinase (LIMK), which regulates actin activity through phosphorylation of cofilin, an actin-depolymerizing factor. Recent studies have found that LIMK/cofilin are targeted by viruses such as HIV-1 for propelling viral intracellular migration. Although inhibiting LIMK1 expression blocks HIV-1 infection, no highly specific LIMK inhibitor is available. This study describes the design, medicinal synthesis, and discovery of small-molecule LIMK inhibitors for blocking HIV-1 and several other viruses and emphasizes the feasibility of developing LIMK inhibitors as broad-spectrum antiviral drugs.

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“…Recent works indicates that LIMK activity is also modulated by HIV-1 viral proteins. LIMK inhibitors have been believed to treat several conditions, including cancer, elevated intraocular pressure (IOP) and glaucoma, pulmonary hypertension and viral diseases [7][8][9][10] . It has also been identified that LIMK1 is activated by HIV-1 in order to initiate viral infection.…”

Section: Introductionmentioning

confidence: 99%

3D QSAR Study on Pyrrolopyrimidines-Based Derivatives as LIM2 Kinase Inhibitors

Balasubramanian¹,

Balupuri²,

Cho³

2015

Journal of the Chosun Natural Science

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LIM kinases belong to the serine/Threonine kinase family. The members of the LIM kinase (LIMK) family include LIMK 1 and 2 which are involved in the regulation of actin polymerisation and microtubule disassembly. LIMK1 was shown to be involved in cancer metastasis, while LIMK2 activation promotes cells cycle progression. Since LIMK2 plays a vital role in many disease conditions such as pulmonary hypertension, cancer and viral diseases, and till date there are not much selective inhibitors been reported, LIMK2 becomes an interesting therapeutic target among the kinases. 3D QSAR study was carried out on a series of pyrrolopyrimidines based derivatives as LIMK2 inhibitors. A reasonable CoMFA (q 2 =0.888; ONC=3; r 2 =0.974) with good statistical values was developed. The developed model was validated using 1000 runs of boostrapping and was found to be predictable. The results of CoMFA contour map analysis suggested that the bulky substitution at R 4 and R 5 position are highly desirable to increase the activity. Similarly, positive substitution at R 3 position is also required to increase the activity. It is also noted that bulky substitution at R 1 position must be avoided. Our results could provide valuable information to enhance the activity of the LIMK2 inhibitors and to design potent pyrrolopyrimidines derivatives.

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HIV-1 proteins join the family of LIM kinase partners. New roads open up for HIV-1 treatment

Cited by 15 publications

References 56 publications

LIM kinases: cofilin and beyond

LIM kinases: cofilin and beyond

Discovery of Novel Small-Molecule Inhibitors of LIM Domain Kinase for Inhibiting HIV-1

3D QSAR Study on Pyrrolopyrimidines-Based Derivatives as LIM2 Kinase Inhibitors

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