Inthevirion coreofretroviruses, thegenomic RNAis tightly associated withnucleocapsid (NC)protein molecules, forming thenucleocapsid structure. NC protein, ahighly basic protein withtwozincfingers, isindispensable forRNAdimerization, encapsidation andtheinitiation ofreverse transcription inavian, murine andhumanretroviruses. Hereweshowthat NC protein ofHIV-1 (NCp7) andNCp7mutants bindtoDNA fragments representing proviral DNA sequences, forming stable complexes. NCp7andNCp7mutants formhighmolecular weight complexes withlarge DNA fragments andshowcooperativity inbinding tothe DNAs.Itappears thattheconserved basicresidues, andnotthezincfingers, areimportant forcomplex formation. Inaddition, NCp7andseveral NCp7mutants protect DNAsfromnuclease digestion while theDNA endsappear tobepoorly protected. NCp7hasbeen foundtobindtostrong stopcDNA,theinitial product ofreverse transcription, andtopromote theannealing ofthis cDNAtoHIV-1 RNAcorresponding tothe3'end ofthegenome.Inaddition, NCp7slightly stimulates an invitro INcleavage assay. Theseresults indicate that theinteractions between NCp7andproviral DNAmay beimportant during provirus synthesis and/or prior to integration.

Interactions between HIV-1nucleocapsid protein andviral DNA may haveimportant functions intheviral life cycle

NCp7: targeting a multitasking protein for next-generation anti-HIV drug development part 1: covalent inhibitors.

Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising therapeutic targets. During fasting, activation of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPARα directly upregulates the long non-coding RNA gene Gm15441 through PPARα binding sites within its promoter. Gm15441 expression suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, decreases TXNIP-stimulated NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, caspase-1 (CASP1) cleavage, and proinflammatory interleukin 1β (IL1B) maturation. Gm15441-null mice were developed and shown to be more susceptible to NLRP3 inflammasome activation and to exhibit elevated CASP1 and IL1B cleavage in response to PPARα agonism and fasting. These findings provide evidence for a mechanism by which PPARα attenuates hepatic inflammasome activation in response to metabolic stress through induction of lncRNA Gm15441.

/pdf/long-non-coding-rna-gm15441-attenuates-hepatic-inflammasome-pyp5i6d6yf.pdf

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting.

Portal vein tumor thrombosis (PVTT) is one of the most common complications in hepatocellular carcinoma (HCC) HCC with PVTT usually indicates poor prognosis, which has a number of characteristics including a rapidly progressive disease course, worse liver function, complications connected with portal hypertension, and poorer tolerance to treatment The exact mechanisms of PVTT remain unknown, even though some concerned signal transduction or molecular pathways have been identified In western countries, sorafenib is the only recommended therapeutic strategy regardless of PVTT types However, multiple treatment options including transhepatic arterial chemoembolization, hepatectomy, radiotherapy, and sorafenib available in the clinic In this review, we enumerate and discuss therapeutics against patients with HCC having PVTT available in the clinic and put forward directions for future research

Comprehensive treatments for hepatocellular carcinoma with portal vein tumor thrombosis

Hepatocellular carcinoma (HCC) is one of the most common cancers with high incidence and mortality. However, the underlying mechanisms of HCC still remain unclear. Eukaryotic translation initiation factors (eIFs) have a substantial effect on tumor development. In this study, we were aimed to investigate the role of eukaryotic translation initiation factor 4 gamma 2 (EIF4G2) in HCC. Western blot (WB) of 30 paired HCC tissues and tissue microarrays (TMAs) conducted by immunohistochemistry (IHC) in 89 paired HCC samples were performed to assess EIF4G2 expression. Clone formation, real-time cell analysis (RTCA), wound healing and transwell assays were adopted to evaluate the role of EIF4G2 on HCC cell proliferation, migration and invasion abilities. The function of EIF4G2 in HCC tumor growth was assessed in a xenograft nude mouse model in vivo. The regulation of EIF4G2 by miR-144-3p was performed by luciferase reporter assay and WB. The EIF4G2 protein was clearly upregulated in HCC tissues, and high EIF4G2 expression was closely related to HCC prognosis. EIF4G2 silencing could inhibit HCC cell growth and metastasis in vitro, and suppress tumorigenesis in vivo by repressing the ERK signaling pathway. The results of luciferase reporter assays, WB and IHC staining verified that EIF4G2 was negatively regulated by miR-144. And re-expression of EIF4G2 could partially reverse the inhibiting effect of miR-144 in HCC. In summary, our study revealed the role of EIF4G2 in HCC development via the activation of the ERK pathway. We also found that EIF4G2 could be negatively regulated by the tumor suppressor miR-144. Our investigations indicated that EIF4G2 might be a promising therapeutic target in HCC.

/pdf/mir-144-3p-mediated-dysregulation-of-eif4g2-contributes-to-2rr39woqyf.pdf

MiR-144-3p-mediated dysregulation of EIF4G2 contributes to the development of hepatocellular carcinoma through the ERK pathway.

Preclinical evaluation of a mercaptobenzamide and its prodrug for NCp7-targeted inhibition of human immunodeficiency virus.

Hepatocellular carcinoma (HCC) is the third leading form of cancer worldwide, and its incidence is increasing rapidly in the United States, tripling over the past 3 decades. The current chemotherapeutic strategies against localized and metastatic HCC are ineffective. Here we report that 6-methoxyethylamino-numonafide (MEAN) is a potent growth inhibitor of murine xenografts of 2 human HCC cell lines. At the same dose and with the same treatment strategies, MEAN was more efficacious in inhibiting tumor growth in mice than sorafenib, the only approved drug for HCC. Treatment by MEAN at an effective dose for 6 wk was well tolerated by animals. Combined therapy using both sorafenib and MEAN enhanced tumor growth inhibition over monotherapy with either agent. Additional experiments revealed that MEAN inhibited tumor growth through mechanisms distinct from those of either its parent compound, amonafide, or sorafenib. MEAN suppressed C-MYC expression and increased expression of several tumor suppressor genes, including Src homology region 2 domain-containing phosphatase-1 (SHP-1) and TXNIP (thioredoxin-interacting protein). As an encouraging feature for envisioned clinical application, the IC50 of MEAN was not significantly changed in several drug-resistant cell lines with activated P-glycoprotein drug efflux pumps compared to drug-sensitive parent cells, demonstrating the ability of MEAN to be effective in cells resistant to existing chemotherapy regimens. MEAN is a promising candidate for clinical development as a single-agent therapy or in combination with sorafenib for the management of HCC.-Liu, Y., Lou, G., Norton, J. T., Wang, C., Kandela, I., Tang, S., Shank, N. I., Gupta, P., Huang, M., Avram, M. J., Green, R., Mazar, A., Appella, D., Chen, Z., Huang, S. 6-Methoxyethylamino-numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.201700306RR

6-Methoxyethylamino-numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib.

Human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein 7 (NCp7), a zinc finger protein, plays critical roles in viral replication and maturation and represents an attractive target for drug development. However, development of drug-like molecules that inhibit NCp7 has been a significant challenge. In this report, a series of novel 2-mercaptobenzamide prodrugs have been investigated for anti-HIV activity in the context of NCp7 inactivation. The molecules are synthesized from the corresponding thiosalicylic acids, and they are all crystalline solids and stable at room temperature. Derivatives with a range of amide side chains and aromatic substituents were synthesized and screened for anti-HIV activity. Wide ranges of antiviral activity were observed, with IC50 values ranging from 1 to 100 μM depending on subtle changes to the substituents on the aromatic ring and the sidechain. Results from these structure-activity relationships were fit to a probable mode of intracellular activation and interaction with NCp7 to explain variations in antiviral activity. Our strategy to make a series of mercaptobenzamide prodrugs represents a general new direction to make libraries that can be screened for anti-HIV activity.

/pdf/probing-mercaptobenzamides-as-hiv-inactivators-via-dn5r9uxstk.pdf

Nathaniel I. Shank

Papers

Preclinical evaluation of a mercaptobenzamide and its prodrug for NCp7-targeted inhibition of human immunodeficiency virus.

6-Methoxyethylamino-numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib.

Probing Mercaptobenzamides as HIV Inactivators via Nucleocapsid Protein 7.