Amenamevir, a Helicase-Primase Inhibitor, for the Optimal Treatment of Herpes Zoster

Total Page:16

File Type:pdf, Size:1020Kb

Amenamevir, a Helicase-Primase Inhibitor, for the Optimal Treatment of Herpes Zoster viruses Review Amenamevir, a Helicase-Primase Inhibitor, for the Optimal Treatment of Herpes Zoster Kimiyasu Shiraki 1,*, Shinichiro Yasumoto 2, Nozomu Toyama 3 and Hiroaki Fukuda 4 1 Faculty of Nursing, Senri Kinran University, 5-25-1 Fujishirodai, Suita, Osaka 565-0873, Japan 2 Yasumoto Dermatology Clinic, Tsukushino, Fukuoka 818-0083, Japan; [email protected] 3 Toyama Dermatologic Clinic, Aburatsu, Nichinan City, Miyazaki 887-0001, Japan; [email protected] 4 Maruho Co., Ltd., Nakatsu, Osaka 531-0071, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-6-6872-7139 Abstract: Acyclovir, valacyclovir, and famciclovir are used for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Helicase-primase inhibitors (HPIs) inhibit replication fork progression that separates double DNA strands into two single strands during DNA synthesis. The HPIs amenamevir and pritelivir have novel mechanisms of anti-herpetic action, and their once-daily administration has clinical efficacy for genital herpes. Among HPIs, amenamevir has anti-VZV activity. The concentrations of HSV-1 and VZV required for the 50% plaque reduction of amenamevir were 0.036 and 0.047 µM, respectively. We characterized the features of amenamevir regarding its mechanism, resistance, and synergism with acyclovir. Its antiviral activity was not influenced by the viral replication cycle, in contrast to acyclovir. A clinical trial of amenamevir for herpes zoster demonstrated its non-inferiority to valacyclovir. To date, amenamevir has been successfully used in over 1,240,000 patients with herpes zoster in Japan. Post-marketing surveillance of amenamevir in Japan reported side effects with significant potential risk identified by the Japanese Risk Management Plan, including thrombocytopenia, gingival bleeding, and palpitations, although Citation: Shiraki, K.; Yasumoto, S.; none of these were serious. The clinical efficacy and safety profiles of amenamevir were established Toyama, N.; Fukuda, H. Amenamevir, a Helicase-Primase Inhibitor, for the in patients with herpes zoster. Therefore, amenamevir as an HPI opens a new era of anti-herpes Optimal Treatment of Herpes Zoster. therapy. Viruses 2021, 13, 1547. https:// doi.org/10.3390/v13081547 Keywords: amenamevir; helicase-primase inhibitor; herpes simplex virus; varicella-zoster virus; herpes zoster; antivirals Academic Editor: Barry J. Margulies Received: 30 June 2021 Accepted: 3 August 2021 1. Introduction Published: 5 August 2021 Varicella-zoster virus (VZV) infection, which causes varicella and herpes zoster, is treated with antivirals. Elion developed acyclovir for systemic administration to treat Publisher’s Note: MDPI stays neutral herpes simplex virus (HSV) and VZV infections [1–3]. Penciclovir, valacyclovir, and with regard to jurisdictional claims in famciclovir are currently used for preventing and treating HSV and VZV infections [4]. published maps and institutional affil- The antiherpetic drugs valacyclovir (acyclovir) and famciclovir (penciclovir) have iations. been developed for the treatment and prevention of apparent HSV and VZV infections. New antiherpetic drugs with different mechanisms of action have been developed as novel helicase-primase (HP) inhibitors (HPIs) of HSV and VZV. Double-stranded DNA is sepa- rated into two single strands (replication fork) before DNA synthesis, and complementary Copyright: © 2021 by the authors. strands are synthesized from each DNA strand to produce two new double-stranded DNA Licensee MDPI, Basel, Switzerland. molecules during DNA replication, as shown in Figure1. The HP complex unwinds viral This article is an open access article DNA at the replication fork, separating double-stranded DNA into two single strands, and distributed under the terms and synthesizing RNA primers followed by Okazaki fragments in the lagging strand for DNA conditions of the Creative Commons synthesis. Then, DNA polymerase initiates complementary DNA synthesis in the two Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ separated DNA strands. The HP complex consists of three proteins: HSV UL5/VZVORF55 4.0/). (helicase), HSV UL52/VZVORF6 (primase), and HSV UL8/VZVORF52 (cofactor). Viruses 2021, 13, 1547. https://doi.org/10.3390/v13081547 https://www.mdpi.com/journal/viruses Viruses 2021, 13, x FOR PEER REVIEW 2 of 21 Viruses 2021, 13, 1547 HSV UL5/VZVORF55 (helicase), HSV UL52/VZVORF6 (primase), and HSV 2 of 21 UL8/VZVORF52 (cofactor). Figure 1. The viral helicase primase (HP) complex in viral DNA synthesis (modified from [5]). The figure shows the role of Figure 1. The viral helicase primase (HP) complex in viral DNA synthesis (modified from [5]). The figure shows the role the HPof the complex HP complex (UL5, (UL5, UL8, UL8, and UL52and UL52 of HSV of HSV and and ORF55, ORF55, ORF6, ORF6, and and ORF52 ORF52 of of VZV), VZV), the the DNA DNA polymerasepolymerase complex complex (UL42 and UL30(UL42 ofand HSV UL30 and of ORF28HSV and of VZV:ORF28 DNA of VZV: polymerase), DNA polymerase) and the, ICP8and the single-stranded ICP8 single-stranded DNA bindingDNA binding protein protein of HSV of (ORF29 of VZV).HSV (ORF29 HSV UL5 of VZV). and VZVORF55HSV UL5 and (helicase) VZVORF55 relax (helicase) double-stranded relax double-strande DNA andd DNA separate and separate double double strands strands into into two single strands,two single forming strands, a replication forming a fork. replication HSV UL52 fork. HSV and VZVORF55UL52 and VZVORF55 (primase) (primase) synthesize synthesize RNA primers RNA primers (followed (followed by Okazaki by Okazaki fragments) for lagging strand DNA synthesis. DNA polymerase contains intrinsic ribonuclease H (RNase H) fragments)activity forthat lagging specifically strand degrades DNA RNA/DNA synthesis. heteroduplexes DNA polymerase formed contains from RNA intrinsic primer ribonuclease-Okazaki fragment H (RNases and the H) activitytem- that specificallyplate DNA degrades complex. RNA/DNA DNA polymerase heteroduplexes and its accessory formed protein from (UL42) RNA primer-Okazakibind to each single fragments strand and andsynthesize the template com- DNA complex.plementary DNA DNA polymerase to each strand and itsof the accessory replication protein fork. The (UL42) single bind-stranded to each DNA single binding strand protein and with synthesize helix destabilizing complementary DNAactivit to eachy, ICP8 strand (UL29 ofthe of HSV replication and VZV), fork. binds The to single-stranded a single-stranded DNA template binding DNA protein with withhelix helixdestabilizing destabilizing activity activity,. The ICP8 arrows indicate the direction of movement of the DNA replication proteins. (UL29 of HSV and VZV), binds to a single-stranded template DNA with helix destabilizing activity. The arrows indicate the direction of movement of the DNAAreplication 2-amino thiazole proteins. compound, T157602, was reported as an HSV-2 HPI [6] and there- after two HPIs, BILS 22 BS and Bay 57-1293 (pritelivir), were shown to have anti-HSV activityA 2-amino in vitro and thiazole therapeutic compound, activity in T157602, murine HSV was models reported [7–9] as. Next, an HSV-2 three classes HPI [6] and thereafterof herpesvirus two HPIs, HPIs BILSwere 22 developed BS and Bay: thiazole 57-1293 urea (pritelivir), (pritelivir were [9]) shown, 2-amino to- havethiazol- anti-HSV activityylphenylin derivatives vitro and therapeutic(BILS 179 BS activity [8]), and in murineoxadiazolylphenyl HSV models type [7 –(9ASP2151]. Next,, threeame- classes ofnamevir herpesvirus) [10]. Amenamevir HPIs were developed: has anti-HSV thiazole and anti urea-VZV (pritelivir activity, while, [9]), 2-amino-thiazolylphenyl in contrast, prite- derivativeslivir and BILS (BILS 22 BS 179 have BS anti [8]),-HSV and activity oxadiazolylphenyl but lack anti-VZV type activity (ASP2151,. Clinical amenamevir) studies of [10]. AmenamevirHPIs on genital has herpes anti-HSV using andamenamevir anti-VZV and activity, pritelivir while, have in been contrast, conducted pritelivir [11–13] and. BILS 22 BS haveWe anti-HSVcharacterized activity the profile but lack of the anti-VZV anti-HSV activity.and anti- ClinicalVZV activities studies of amenamevir of HPIs on genital herpes[14–18] using. The antiviral amenamevir activity and of amenamevir pritelivir have was beennot influenced conducted by [viral11–13 DNA]. synthesis, althoughWe characterized that of acyclovir the was profile attenuated of the[17,18] anti-HSV. Amenamevir and anti-VZVwas licensed activities for the treat- of amena- ment of herpes zoster on the basis of a clinical trial on herpes zoster treatment in Septem- mevir [14–18]. The antiviral activity of amenamevir was not influenced by viral DNA ber 2017 [19]. In this review, we focus on the anti-HSV and anti-VZV activities of ame- synthesis, although that of acyclovir was attenuated [17,18]. Amenamevir was licensed for namevir and discuss the differences in its antiviral activity compared with acyclovir. the treatment of herpes zoster on the basis of a clinical trial on herpes zoster treatment in September 2017 [19]. In this review, we focus on the anti-HSV and anti-VZV activities of amenamevir and discuss the differences in its antiviral activity compared with acyclovir. 2. Role of HP in DNA Synthesis Double-stranded DNA needs to be separated into two single strands (replication fork) for DNA synthesis, and these two separated complementary strands proceed to form two new double-stranded DNA molecules during DNA
Recommended publications
  • “Amenalief® Tab. 200Mg” in Japan
    News Release July 3, 2017 Maruho Co., Ltd. Maruho receives manufacturing and marketing approval for Anti-Herpes Virus Agent “Amenalief® Tab. 200mg” in Japan Osaka (Japan), July 3, 2017 – Maruho Co., Ltd (“Maruho”, Head Office: Osaka, Japan, President and CEO: Koichi Takagi) announces that today it has received manufacturing and marketing approval from the Japanese Ministry of Health, Labor and Welfare (MHLW), for anti-herpes virus agent “Amenalief® Tab. 200mg” (INN: amenamevir) (hereinafter referred to as “the product”) for the treatment of herpes zoster (shingles) in Japan. The product is an anti-herpes virus agent with a novel mechanism of action created by Astellas Pharma Inc. (“Astellas”; Head Office: Tokyo, President and CEO: Yoshihiko Hatanaka). The product has been observed to inhibit the proliferation of the varicella-zoster virus (hereinafter VZV) by inhibiting the activity of the helicase-primase complex, which is essential for viral DNA replication. In August 2012, Maruho and Astellas agreed on a license agreement for the development and commercialization of the product in Japan, and Maruho has been progressing its development. Herpes zoster (shingles) is a disease caused by reactivation of the chickenpox VZV in latently-infected nerve ganglia. The main treatment for shingles is anti-herpes virus agents. The product is proven to be effective against VZV when administered once a day after meals. Also, since most of the product is excreted in feces, it is not necessary to adjust the dosage and administration according to creatinine clearance, an indicator of kidney function. Maruho hopes the product will contribute to the expansion of treatment options and improvement in adherence for the treatment of shingles in Japan.
    [Show full text]
  • Inclusion and Exclusion Criteria for Each Key Question
    Supplemental Table 1: Inclusion and exclusion criteria for each key question Chronic HBV infection in adults ≥ 18 year old (detectable HBsAg in serum for >6 months) Definition of disease Q1 Q2 Q3 Q4 Q5 Q6 Q7 HBV HBV infection with infection and persistent compensated Immunoactive Immunotolerant Seroconverted HBeAg HBV mono-infected viral load cirrhosis with Population chronic HBV chronic HBV from HBeAg to negative population under low level infection infection anti-HBe entecavir or viremia tenofovir (<2000 treatment IU/ml) Adding 2nd Stopped antiviral therapy antiviral drug Interventions and Entecavir compared Antiviral Antiviral therapy compared to continued compared to comparisons to tenofovir therapy therapy continued monotherapy Q1-2: Clinical outcomes: Cirrhosis, decompensated liver disease, HCC and death Intermediate outcomes (if evidence on clinical outcomes is limited or unavailable): HBsAg loss, HBeAg seroconversion and Outcomes HBeAg loss Q3-4: Cirrhosis, decompensated liver disease, HCC, relapse (viral and clinical) and HBsAg loss Q5: Renal function, hypophosphatemia and bone density Q6: Resistance, flare/decompensation and HBeAg loss Q7: Clinical outcomes: Cirrhosis, decompensated liver disease, HCC and death Study design RCT and controlled observational studies Acute HBV infection, children and pregnant women, HIV (+), HCV (+) or HDV (+) persons or other special populations Exclusions such as hemodialysis, transplant, and treatment failure populations. Co treatment with steroids and uncontrolled studies. Supplemental Table 2: Detailed Search Strategy: Ovid Database(s): Embase 1988 to 2014 Week 37, Ovid MEDLINE(R) In-Process & Other Non- Indexed Citations and Ovid MEDLINE(R) 1946 to Present, EBM Reviews - Cochrane Central Register of Controlled Trials August 2014, EBM Reviews - Cochrane Database of Systematic Reviews 2005 to July 2014 Search Strategy: # Searches Results 1 exp Hepatitis B/dt 26410 ("hepatitis B" or "serum hepatitis" or "hippie hepatitis" or "injection hepatitis" or 2 178548 "hepatitis type B").mp.
    [Show full text]
  • Saccharomyces Rrm3p, a 5 to 3 DNA Helicase That Promotes Replication
    Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Saccharomyces Rrm3p, a 5؅ to 3؅ DNA helicase that promotes replication fork progression through telomeric and subtelomeric DNA Andreas S. Ivessa,1 Jin-Qiu Zhou,1,2 Vince P. Schulz, Ellen K. Monson, and Virginia A. Zakian3 Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544-1014, USA In wild-type Saccharomyces cerevisiae, replication forks slowed during their passage through telomeric ؅ C1–3A/TG1–3 tracts. This slowing was greatly exacerbated in the absence of RRM3, shown here to encode a 5 ,to 3؅ DNA helicase. Rrm3p-dependent fork progression was seen at a modified Chromosome VII-L telomere at the natural X-bearing Chromosome III-L telomere, and at Y؅-bearing telomeres. Loss of Rrm3p also resulted in replication fork pausing at specific sites in subtelomeric DNA, such as at inactive replication origins, and at internal tracts of C1–3A/TG1–3 DNA. The ATPase/helicase activity of Rrm3p was required for its role in telomeric and subtelomeric DNA replication. Because Rrm3p was telomere-associated in vivo, it likely has a direct role in telomere replication. [Key Words: Telomere; helicase; telomerase; replication; RRM3; yeast] Received February 7, 2002; revised version accepted April 10, 2002. Telomeres are the natural ends of eukaryotic chromo- Because conventional DNA polymerases cannot repli- somes. In most organisms, the very ends of chromo- cate the very ends of linear DNA molecules, special somes consist of simple repeated sequences. For ex- mechanisms are required to prevent the loss of terminal ample, Saccharomyces cerevisiae chromosomes end in DNA.
    [Show full text]
  • Which Drugs Are Most Effective for Recurrent Herpes Labialis?
    Evidence-based answers from the clinical inquiries Family Physicians Inquiries Network Eiko Tubridy, MD; Gary Kelsberg, MD Valley Family Residency Which drugs are most Program, Renton, Wash Leilani St Anna, MLIS, effective for recurrent AHIP University of Washington Health Sciences Libraries, herpes labialis? Seattle AssistanT EDITOR EvidEncE-basEd answEr Jon O. neher, MD Valley Family Residency daily oral acyclovir or vala- ing to the agent used: valacyclovir reduces Program, Renton, Wash A cyclovir may help prevent her- both healing time and duration of pain, pes simplex labialis (HSL) recurrences famciclovir reduces both in one dosage (strength of recommendation [SOR]: B, form but not another, and acyclovir reduces meta-analysis of randomized controlled only pain duration (SOR: B, single RCTs). trials [RCTs] with heterogeneous results). Several topical medications (acyclovir, No trials compare oral or topical treat- penciclovir, docosanol) modestly decrease ments for HSL outbreaks against each oth- healing time and pain duration—typically er. Oral antivirals modestly reduce healing by less than a day—and require multiple time and duration of pain, varying accord- doses per day (SOR: B, multiple RCTs). Evidence summary The authors of the meta-analysis noted A systematic review and meta-analysis of the that although 9 studies favored the use of an effectiveness of oral and topical nucleoside antiviral drug, only 4 showed statistically sig- antiviral agents to prevent recurrent HSL in nificant differences when compared with pla- immunocompetent people found 11 RCTs cebo, and none of them had a low risk of bias. with a total of 1250 patients that compared They concluded that the review supported us- an active drug against placebo.1 The medi- ing oral acyclovir and valacyclovir to prevent cations were topical 5% acyclovir, topical 1% recurrent HSL.1 penciclovir, and oral acyclovir, valacyclovir, or famciclovir in various doses.
    [Show full text]
  • Aicuris Granted Fast Track Designation by U.S. FDA for Oral Pritelivir for Treatment of HSV Infections in Immunocompromised Adults
    AiCuris Granted Fast Track Designation by U.S. FDA for Oral Pritelivir for Treatment of HSV Infections in Immunocompromised Adults Wuppertal, August 01, 2017 - AiCuris Anti-infective Cures GmbH, a leading company in the discovery and development of drugs against infectious diseases, today announced that the Company has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for oral pritelivir, AiCuris’ lead candidate for the treatment of acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infections in immunocompromised adults. Fast track is a process designed to facilitate the development, expedite the review and accelerate the approval process of drugs to treat serious conditions and fill an unmet medical need, with the purpose of getting important new drugs to patients sooner. Oral pritelivir, a small molecule helicase-primase inhibitor with a novel mode of action, is currently in a clinical phase 2 study, called PRIOH-1, in the U.S. to evaluate the product candidate’s efficacy and safety compared to i.v. foscarnet, a virostatic agent which is used mainly for the treatment of herpes viruses resistant to other antiviral drugs. In a prior phase 2 study, oral pritelivir showed to significantly improve the suppression of viral shedding compared to the current standard of care for genital HSV-2 infections, the nucleoside analog valacyclovir. The results of this study were published in the Journal of the American Medical Association (JAMA) earlier this year. “The decision by the FDA to grant fast track designation to oral pritelivir underscores that our product might fill the major need for innovative, more efficacious therapies for immunocompromised patients with HSV infections that have become resistant to standard treatments,” said Dr.
    [Show full text]
  • The Architecture of a Eukaryotic Replisome
    The Architecture of a Eukaryotic Replisome Jingchuan Sun1,2, Yi Shi3, Roxana E. Georgescu3,4, Zuanning Yuan1,2, Brian T. Chait3, Huilin Li*1,2, Michael E. O’Donnell*3,4 1 Biosciences Department, Brookhaven National Laboratory, Upton, New York, USA 2 Department of Biochemistry & Cell Biology, Stony Brook University, Stony Brook, New York, USA. 3 The Rockefeller University, 1230 York Avenue, New York, New York, USA. 4 Howard Hughes Medical Institute *Correspondence and requests for materials should be addressed to M.O.D. ([email protected]) or H.L. ([email protected]) ABSTRACT At the eukaryotic DNA replication fork, it is widely believed that the Cdc45-Mcm2-7-GINS (CMG) helicase leads the way in front to unwind DNA, and that DNA polymerases (Pol) trail behind the helicase. Here we use single particle electron microscopy to directly image a replisome. Contrary to expectations, the leading strand Pol ε is positioned ahead of CMG helicase, while Ctf4 and the lagging strand Pol α-primase (Pol α) are behind the helicase. This unexpected architecture indicates that the leading strand DNA travels a long distance before reaching Pol ε, it first threads through the Mcm2-7 ring, then makes a U-turn at the bottom to reach Pol ε at the top of CMG. Our work reveals an unexpected configuration of the eukaryotic replisome, suggests possible reasons for this architecture, and provides a basis for further structural and biochemical replisome studies. INTRODUCTION DNA is replicated by a multi-protein machinery referred to as a replisome 1,2. Replisomes contain a helicase to unwind DNA, DNA polymerases that synthesize the leading and lagging strands, and a primase that makes short primed sites to initiate DNA synthesis on both strands.
    [Show full text]
  • Multipurpose Tenofovir Disoproxil Fumarate Electrospun Fibers for the Prevention of HIV-1 and HSV-2 Infections
    University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 8-2016 Multipurpose tenofovir disoproxil fumarate electrospun fibers for the prevention of HIV-1 and HSV-2 infections. Kevin Tyo Follow this and additional works at: https://ir.library.louisville.edu/etd Part of the Other Chemicals and Drugs Commons, Polymer Chemistry Commons, Preventive Medicine Commons, and the Virus Diseases Commons Recommended Citation Tyo, Kevin, "Multipurpose tenofovir disoproxil fumarate electrospun fibers for the prevention of HIV-1 and HSV-2 infections." (2016). Electronic Theses and Dissertations. Paper 2486. https://doi.org/10.18297/etd/2486 This Master's Thesis is brought to you for free and open access by ThinkIR: The University of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The University of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. MULTIPURPOSE TENOFOVIR DISOPROXIL FUMARATE ELECTROSPUN FIBERS FOR THE PREVENTION OF HIV-1 AND HSV-2 INFECTIONS By Kevin Tyo B.S. Virginia Tech, 2010 A Thesis Submitted to the Faculty of the School of Medicine of the University of Louisville In Partial Fulfillment of the Requirement for the Degree of Master of Science In Pharmacology and Toxicology Department of Pharmacology and Toxicology School of Medicine University of Louisville Louisville, KY August, 2016 MULTIPURPOSE TENOFOVIR DISOPROXIL FUMARATE ELECTROSPUN FIBERS FOR THE PREVENTION OF HIV-1 AND HSV-2 INFECTIONS By Kevin Tyo B.S.
    [Show full text]
  • The Biochemical Activities of the Saccharomyces Cerevisiae Pif1 Helicase Are Regulated by Its N-Terminal Domain
    G C A T T A C G G C A T genes Article The Biochemical Activities of the Saccharomyces cerevisiae Pif1 Helicase Are Regulated by Its N-Terminal Domain David G. Nickens y, Christopher W. Sausen y and Matthew L. Bochman * Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, IN 47405, USA; [email protected] (D.G.N.); [email protected] (C.W.S.) * Correspondence: [email protected] These authors contributed equally to this work. y Received: 31 March 2019; Accepted: 20 May 2019; Published: 28 May 2019 Abstract: Pif1 family helicases represent a highly conserved class of enzymes involved in multiple aspects of genome maintenance. Many Pif1 helicases are multi-domain proteins, but the functions of their non-helicase domains are poorly understood. Here, we characterized how the N-terminal domain (NTD) of the Saccharomyces cerevisiae Pif1 helicase affects its functions both in vivo and in vitro. Removal of the Pif1 NTD alleviated the toxicity associated with Pif1 overexpression in yeast. Biochemically, the N-terminally truncated Pif1 (Pif1DN) retained in vitro DNA binding, DNA unwinding, and telomerase regulation activities, but these activities differed markedly from those displayed by full-length recombinant Pif1. However, Pif1DN was still able to synergize with the Hrq1 helicase to inhibit telomerase activity in vitro, similar to full-length Pif1. These data impact our understanding of Pif1 helicase evolution and the roles of these enzymes in the maintenance of genome integrity. Keywords: DNA helicase; Saccharomyces cerevisiae; Pif1; telomerase; telomere 1. Introduction DNA helicases are enzymes that couple DNA binding and ATP hydrolysis to unwind double-stranded DNA (dsDNA) into its component single strands [1].
    [Show full text]
  • Exploring the Non-Canonical Functions of Metabolic Enzymes Peiwei Huangyang1,2 and M
    © 2018. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2018) 11, dmm033365. doi:10.1242/dmm.033365 REVIEW SPECIAL COLLECTION: CANCER METABOLISM Hidden features: exploring the non-canonical functions of metabolic enzymes Peiwei Huangyang1,2 and M. Celeste Simon1,3,* ABSTRACT A key finding from studies of metabolic enzymes is the existence The study of cellular metabolism has been rigorously revisited over the of mechanistic links between their nuclear localization and the past decade, especially in the field of cancer research, revealing new regulation of transcription. By modulating gene expression, insights that expand our understanding of malignancy. Among these metabolic enzymes themselves facilitate adaptation to rapidly insights isthe discovery that various metabolic enzymes have surprising changing environments. Furthermore, they can directly shape a ’ activities outside of their established metabolic roles, including in cell s epigenetic landscape (Kaelin and McKnight, 2013). the regulation of gene expression, DNA damage repair, cell cycle Strikingly, several metabolic enzymes exert completely distinct progression and apoptosis. Many of these newly identified functions are functions in different cellular compartments. Nuclear fructose activated in response to growth factor signaling, nutrient and oxygen bisphosphate aldolase, for example, directly interacts with RNA ́ availability, and external stress. As such, multifaceted enzymes directly polymerase III to control transcription (Ciesla et al., 2014),
    [Show full text]
  • Efficacy and Safety of Imiquimod for Verruca Planae: a Systematic Review
    Global Dermatology Research Article ISSN: 2056-7863 Efficacy and safety of imiquimod for verruca planae: A systematic review Xin-rui Zhang#, Bi-huan Xiao#, Rui-qun Qi*, and Xing-hua Gao* Department of Dermatology, No 1 Hospital of China Medical University, Shenyang 110001, PR China #These authors contributed equally to this work Abstract Objective: To assess the efficacy and safety of imiquimod for treating verruca planae. Methods: We searched the Pubmed, Cochrane Register of Controlled Trials, EMbase, CBM, CNKI and Wanfang databases (Chinese) to collect randomized controlled trials (RCTs). We screened the retrieved studies according to the predefined inclusion and exclusion criteria, evaluated the quality of include studies, and performed meta-analyses using the Cochrane Collaboration’s RevMan 5.1. Software. Results: Twenty-six RCTs involving 2169 patients with verruca planae were included and assessed. At the end of the 6th and ≥8th week, the effective rate of topical imiquimod was obviously higher than that of control [ RR=1.42, 95%CI (1.27, 1.60), P <0.00001; RR=1.43, 95%CI (1.22,1.67), P<0.00001]. The effective rate of imiquimod cream was higher than tretinoin cream, tazarotene gel and other antiviral drugs. [RR=1.41, 95%CI (1.25, 1.59), P <0.00001; RR=1.76, 95%CI (1.48, 2.10), P<0.00001; RR=1.71, 95%CI (1.29, 2.26), P =0.0002]. However, the effectiverate of imiquimod cream was lower than 5-ALA-PDT (RR=0.6, 95%CI (0.5, 0.71), P<0.00001). Conclusions: The limited evidence demonstrates that topical imiquimod is safe and efficient.
    [Show full text]
  • Treating the Oral Creeper: Herpes
    ISSN: 2574-1241 Volume 5- Issue 4: 2018 DOI: 10.26717/BJSTR.2018.08.001639 Karthik D Yadav. Biomed J Sci & Tech Res Short Communication Open Access Treating the Oral Creeper: Herpes Yadav Karthik D1*, Pai Anuradha2, R Shesha Prasad3, Yaji Anisha4 1M.D.S - Master of Dental surgery, Department of oral medicine and radiology, Bangalore 2HOD & Professor, Department of oral medicine and radiology, The oxford dental college and research center, Bangalore 3M.D.S - Master of Dental surgery, Department of oral medicine and radiology, Senior lecturer, The oxford dental college and research center, Bangalore 4M.D.S – Master of Dental surgery, Department of oral medicine and radiology, Bangalore Received: August 19, 2018; Published: August 24, 2018 *Corresponding author: Karthik D Yadav, 10th Milestone, Bommanahalli, Hosur Road, Bangalore-560 102, India Short Communication combination of all these drugs is more effective in treating HSV The term “herpes” creates panic among the general population. infections than the anesthetic preparations alone. They are also Oral herpes simplex virus is most commonly seen affecting the oral soft tissue region the perioral area [1,2]. They have been categorized treating HSV. Further, ice can be used and lip materials containing into HSV -1 and HSV -2, wherein HSV-1 affects the orofacial region, used with systemic antiviral agents for increased efficacy while cocoa, lanolin and petroleum products have been recommended to most commonly above the waist region and HSV-2 affects the treat recurrent herpes [6]. genital region below the waist. However, change in sexual practices have been the basis for the variations of the virus, affecting the While the use of topical drugs has few adverse effects and are non-conventional regions of the body [3,4].
    [Show full text]
  • Herpes Simplex Virus
    HSV Herpes simplex virus HSV (Herpes simplex virus) can be spread when an infected person is producing and shedding the virus. Herpes simplex can be spread through contact with saliva, such as sharing drinks. Symptoms of herpes simplex virus infection include watery blisters in the skin or mucous membranes of the mouth, lips or genitals. Lesions heal with ascab characteristic of herpetic disease. As neurotropic and neuroinvasive viruses, HSV-1 and -2 persist in the body by becoming latent and hiding from the immune system in the cell bodies of neurons. After the initial or primary infection, some infected people experience sporadic episodes of viral reactivation or outbreaks. www.MedChemExpress.com 1 HSV Inhibitors (Z)-Capsaicin 1-Docosanol (Zucapsaicin; Civamide; cis-Capsaicin) Cat. No.: HY-B1583 (Behenyl alcohol) Cat. No.: HY-B0222 (Z)-Capsaicin is the cis isomer of capsaicin, acts 1-Docosanol is a saturated fatty alcohol used as an orally active TRPV1 agonist, and is used in traditionally as an emollient, emulsifier, and the research of neuropathic pain. thickener in cosmetics, and nutritional supplement; inhibitor of lipid-enveloped viruses including herpes simplex. Purity: 99.96% Purity: ≥98.0% Clinical Data: Launched Clinical Data: Launched Size: 10 mM × 1 mL, 10 mg, 50 mg Size: 500 mg 2-Deoxy-D-glucose 20(R)-Ginsenoside Rh2 (2-DG; 2-Deoxy-D-arabino-hexose; D-Arabino-2-deoxyhexose) Cat. No.: HY-13966 Cat. No.: HY-N1401 2-Deoxy-D-glucose is a glucose analog that acts as 20(R)-Ginsenoside Rh2, a matrix a competitive inhibitor of glucose metabolism, metalloproteinase (MMP) inhibitor, acts as a inhibiting glycolysis via its actions on hexokinase.
    [Show full text]