Mathematical modeling of herpes simplex virus-2 suppression with pritelivir predicts trial outcomes.

Abstract:

:Pharmacokinetic and pharmacodynamic models estimate the potency of antiviral agents but do not capture viral and immunologic factors that drive the natural dynamics of infection. We designed a mathematical model that synthesizes pharmacokinetics, pharmacodynamics, and viral pathogenesis concepts to simulate the activity of pritelivir, a DNA helicase-primase inhibitor that targets herpes simplex virus. Our simulations recapitulate detailed viral kinetic shedding features in five dosage arms of a phase 2 clinical trial. We identify that in vitro estimates of median effective concentration (EC50) are lower than in vivo values for the drug. Nevertheless, pritelivir potently decreases shedding at appropriate doses based on its mode of action and long half-life. Although pritelivir directly inhibits replication in epithelial cells, our model indicates that pritelivir also indirectly limits downstream viral spread from neurons to genital keratinocytes, within genital ulcers, and from ulcer to new mucosal sites of infection. We validate our model based on its ability to predict outcomes in a subsequent trial with a higher dose. The model can therefore be used to optimize dose selection in clinical practice.

journal_name

Sci Transl Med

authors

Schiffer JT,Swan DA,Magaret A,Corey L,Wald A,Ossig J,Ruebsamen-Schaeff H,Stoelben S,Timmler B,Zimmermann H,Melhem MR,Van Wart SA,Rubino CM,Birkmann A

doi

10.1126/scitranslmed.aad6654

subject

Has Abstract

pub_date

2016-02-03 00:00:00

pages

324ra15

issue

324

eissn

1946-6234

issn

1946-6242

pii

8/324/324ra15

journal_volume

8

pub_type

杂志文章
  • Dietary therapy mitigates persistent wake deficits caused by mild traumatic brain injury.

    abstract::Sleep disorders are highly prevalent in patients with traumatic brain injury (TBI) and can significantly impair cognitive rehabilitation. No proven therapies exist to mitigate the neurocognitive consequences of TBI. We show that mild brain injury in mice causes a persistent inability to maintain wakefulness and decrea...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3007092

    authors: Lim MM,Elkind J,Xiong G,Galante R,Zhu J,Zhang L,Lian J,Rodin J,Kuzma NN,Pack AI,Cohen AS

    更新日期:2013-12-11 00:00:00

  • Designing a public square for research computing.

    abstract::A set of principles is proposed for sponsors and developers of research computing applications that can increase the likelihood of successful adoption by researchers. ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3004032

    authors: Masys DR,Harris PA,Fearn PA,Kohane IS

    更新日期:2012-08-29 00:00:00

  • Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia.

    abstract::Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This st...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaz0463

    authors: Vadakekolathu J,Minden MD,Hood T,Church SE,Reeder S,Altmann H,Sullivan AH,Viboch EJ,Patel T,Ibrahimova N,Warren SE,Arruda A,Liang Y,Smith TH,Foulds GA,Bailey MD,Gowen-MacDonald J,Muth J,Schmitz M,Cesano A,Pockley

    更新日期:2020-06-03 00:00:00

  • Key elements for nourishing the translational research environment.

    abstract::Translation in an academic environment requires a support system--people, goals, models, partnerships, and infrastructures--that will push promising basic science and technology projects forward into the clinic. ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaa2049

    authors: Volk HD,Stevens MM,Mooney DJ,Grainger DW,Duda GN

    更新日期:2015-04-08 00:00:00

  • An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model.

    abstract::Measles virus is a highly infectious morbillivirus responsible for major morbidity and mortality in unvaccinated humans. The related, zoonotic canine distemper virus (CDV) induces morbillivirus disease in ferrets with 100% lethality. We report an orally available, shelf-stable pan-morbillivirus inhibitor that targets ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3008517

    authors: Krumm SA,Yan D,Hovingh ES,Evers TJ,Enkirch T,Reddy GP,Sun A,Saindane MT,Arrendale RF,Painter G,Liotta DC,Natchus MG,von Messling V,Plemper RK

    更新日期:2014-04-16 00:00:00

  • Noninvasive 11C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis.

    abstract::Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB), and key TB antimicrobials, including rifampin, have restricted brain penetration. A lack of reliable data on intralesional drug biodistribution in infected tissues has limited pharmacokinetic (PK) modeling efforts to optimize TBM treatments. Curr...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aau0965

    authors: Tucker EW,Guglieri-Lopez B,Ordonez AA,Ritchie B,Klunk MH,Sharma R,Chang YS,Sanchez-Bautista J,Frey S,Lodge MA,Rowe SP,Holt DP,Gobburu JVS,Peloquin CA,Mathews WB,Dannals RF,Pardo CA,Kannan S,Ivaturi VD,Jain SK

    更新日期:2018-12-05 00:00:00

  • Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions.

    abstract::The proinflammatory cytokine interleukin-1β (IL-1β) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1β is mediated by inflammasomes; however, the mechanisms triggering IL-1β processing remain unknown. Recently, cytosolic D...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3002001

    authors: Dombrowski Y,Peric M,Koglin S,Kammerbauer C,Göss C,Anz D,Simanski M,Gläser R,Harder J,Hornung V,Gallo RL,Ruzicka T,Besch R,Schauber J

    更新日期:2011-05-11 00:00:00

  • Changing models of biomedical research.

    abstract::Thanks to the revolutions in information technology, human "-omics" research, and intricate medical device development, academic health centers (AHCs) now have an unparalleled potential to become translational engines that both generate basic science advances and then translate them into human studies and, ultimately,...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000124

    authors: Crowley WF Jr,Gusella JF

    更新日期:2009-10-07 00:00:00

  • It ain't over 'til the fat lady sings.

    abstract::The antiatherogenic drug nicotinic acid (niacin) has antidyslipidemic effects independent of free fatty acid suppression mediated by its receptor HCA₂ (GPR109A) (Lauring et al., this issue). ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.3004445

    authors: Offermanns S

    更新日期:2012-08-22 00:00:00

  • The study is open: Participants are now recruiting investigators.

    abstract::Two U.S. national initiatives have stated emphatically that people will be, not patients, but partners in clinical research. ...

    journal_title:Science translational medicine

    pub_type: 社论

    doi:10.1126/scitranslmed.aaf1001

    authors: Terry SF

    更新日期:2017-01-04 00:00:00

  • Exploiting an Asp-Glu "switch" in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia.

    abstract::Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxi...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aam8460

    authors: Wagner FF,Benajiba L,Campbell AJ,Weïwer M,Sacher JR,Gale JP,Ross L,Puissant A,Alexe G,Conway A,Back M,Pikman Y,Galinsky I,DeAngelo DJ,Stone RM,Kaya T,Shi X,Robers MB,Machleidt T,Wilkinson J,Hermine O,Kung A,St

    更新日期:2018-03-07 00:00:00

  • Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1.

    abstract::Recent studies have established the involvement of the fat mass and obesity-associated gene (FTO) in metabolic disorders such as obesity and diabetes. However, the precise molecular mechanism by which FTO regulates metabolism remains unknown. Here, we used a structure-based virtual screening of U.S. Food and Drug Admi...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aau7116

    authors: Peng S,Xiao W,Ju D,Sun B,Hou N,Liu Q,Wang Y,Zhao H,Gao C,Zhang S,Cao R,Li P,Huang H,Ma Y,Wang Y,Lai W,Ma Z,Zhang W,Huang S,Wang H,Zhang Z,Zhao L,Cai T,Zhao YL,Wang F,Nie Y,Zhi G,Yang YG,Zhang EE,

    更新日期:2019-04-17 00:00:00

  • ATRAID regulates the action of nitrogen-containing bisphosphonates on bone.

    abstract::Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical fem...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aav9166

    authors: Surface LE,Burrow DT,Li J,Park J,Kumar S,Lyu C,Song N,Yu Z,Rajagopal A,Bae Y,Lee BH,Mumm S,Gu CC,Baker JC,Mohseni M,Sum M,Huskey M,Duan S,Bijanki VN,Civitelli R,Gardner MJ,McAndrew CM,Ricci WM,Gurnett CA,D

    更新日期:2020-05-20 00:00:00

  • Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer's disease trigger BACE1 accumulation in axonal swellings.

    abstract::Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer's disease (AD) pathogenesis. Little is known about the mechanisms underlying this initial sign of the pathology. This study proves that Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) loss of function, due to Gga3 g...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aba1871

    authors: Lomoio S,Willen R,Kim W,Ho KZ,Robinson EK,Prokopenko D,Kennedy ME,Tanzi RE,Tesco G

    更新日期:2020-11-18 00:00:00

  • Emerging viral diseases: confronting threats with new technologies.

    abstract::Emerging viral diseases pose ongoing health threats, particularly in an era of globalization; however, new biomedical research technologies such as genome sequencing and structure-based vaccine and drug design have improved our ability to respond to viral threats. ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3009872

    authors: Marston HD,Folkers GK,Morens DM,Fauci AS

    更新日期:2014-09-10 00:00:00

  • STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade.

    abstract::Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce r...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaa4306

    authors: Fu J,Kanne DB,Leong M,Glickman LH,McWhirter SM,Lemmens E,Mechette K,Leong JJ,Lauer P,Liu W,Sivick KE,Zeng Q,Soares KC,Zheng L,Portnoy DA,Woodward JJ,Pardoll DM,Dubensky TW Jr,Kim Y

    更新日期:2015-04-15 00:00:00

  • Porous polymeric platform repairs primates after spinal cord injury.

    abstract::Amine-containing polymers immobilized on mesh and placed at trauma sites scavenge biomolecules that initiate a damaging immune response. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aam6068

    authors: Ulery BD

    更新日期:2017-02-22 00:00:00

  • Drug effectiveness explained: the mathematics of antiviral agents for HIV.

    abstract::Antiretroviral therapy has improved the quality and length of life of millions of individuals affected by human immunodeficiency virus type 1 (HIV-1). The capacity of these drugs to indefinitely suppress HIV-which has a well-known capacity for escaping antiviral pressures-is surprising. In this issue of Science Transl...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.3002656

    authors: Perelson AS,Deeks SG

    更新日期:2011-07-13 00:00:00

  • Epidermal electronics for noninvasive, wireless, quantitative assessment of ventricular shunt function in patients with hydrocephalus.

    abstract::Hydrocephalus is a common and costly neurological condition caused by the overproduction and/or impaired resorption of cerebrospinal fluid (CSF). The current standard of care, ventricular catheters (shunts), is prone to failure, which can result in nonspecific symptoms such as headaches, dizziness, and nausea. Current...

    journal_title:Science translational medicine

    pub_type: 临床试验,杂志文章

    doi:10.1126/scitranslmed.aat8437

    authors: Krishnan SR,Ray TR,Ayer AB,Ma Y,Gutruf P,Lee K,Lee JY,Wei C,Feng X,Ng B,Abecassis ZA,Murthy N,Stankiewicz I,Freudman J,Stillman J,Kim N,Young G,Goudeseune C,Ciraldo J,Tate M,Huang Y,Potts M,Rogers JA

    更新日期:2018-10-31 00:00:00

  • A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration.

    abstract::Retinal pigment epithelium (RPE) dysfunction and loss are a hallmark of non-neovascular age-related macular degeneration (NNAMD). Without the RPE, a majority of overlying photoreceptors ultimately degenerate, leading to severe, progressive vision loss. Clinical and histological studies suggest that RPE replacement str...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aao4097

    authors: Kashani AH,Lebkowski JS,Rahhal FM,Avery RL,Salehi-Had H,Dang W,Lin CM,Mitra D,Zhu D,Thomas BB,Hikita ST,Pennington BO,Johnson LV,Clegg DO,Hinton DR,Humayun MS

    更新日期:2018-04-04 00:00:00

  • IgH sequences in common variable immune deficiency reveal altered B cell development and selection.

    abstract::Common variable immune deficiency (CVID) is the most common symptomatic primary immune deficiency, affecting ~1 in 25,000 persons. These patients suffer from impaired antibody responses, autoimmunity, and susceptibility to lymphoid cancers. To explore the cellular basis for these clinical phenotypes, we conducted high...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aab1216

    authors: Roskin KM,Simchoni N,Liu Y,Lee JY,Seo K,Hoh RA,Pham T,Park JH,Furman D,Dekker CL,Davis MM,James JA,Nadeau KC,Cunningham-Rundles C,Boyd SD

    更新日期:2015-08-26 00:00:00

  • Rapid emergence of protease inhibitor resistance in hepatitis C virus.

    abstract::About 170 million people worldwide are infected with hepatitis C virus (HCV). The current standard therapy leads to sustained viral elimination in only approximately 50% of the treated patients. Telaprevir, an HCV protease inhibitor, has substantial antiviral activity in patients with chronic HCV infection. However, i...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000544

    authors: Rong L,Dahari H,Ribeiro RM,Perelson AS

    更新日期:2010-05-05 00:00:00

  • Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure.

    abstract::Urea, the toxic end product of protein catabolism, is elevated in end-stage renal disease (ESRD), although it is unclear whether or how it contributes to disease. Urea can promote the carbamylation of proteins on multiple lysine side chains, including human albumin, which has a predominant carbamylation site on Lys(54...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3005218

    authors: Berg AH,Drechsler C,Wenger J,Buccafusca R,Hod T,Kalim S,Ramma W,Parikh SM,Steen H,Friedman DJ,Danziger J,Wanner C,Thadhani R,Karumanchi SA

    更新日期:2013-03-06 00:00:00

  • Targeting membrane-expressed IgE B cell receptor with an antibody to the M1 prime epitope reduces IgE production.

    abstract::Elevated serum levels of both total and allergen-specific immunoglobulin E (IgE) correlate with atopic diseases such as allergic rhinitis and allergic asthma. Neutralization of IgE by anti-IgE antibodies can effectively treat allergic asthma. Preclinical studies indicate that targeting membrane IgE-positive cells with...

    journal_title:Science translational medicine

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.1126/scitranslmed.3008961

    authors: Gauvreau GM,Harris JM,Boulet LP,Scheerens H,Fitzgerald JM,Putnam WS,Cockcroft DW,Davis BE,Leigh R,Zheng Y,Dahlén B,Wang Y,Maciuca R,Mayers I,Liao XC,Wu LC,Matthews JG,O'Byrne PM

    更新日期:2014-07-02 00:00:00

  • A vitamin to D-crease sunburn.

    abstract::High doses of oral vitamin D3 attenuate skin inflammation following experimentally induced sun damage. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aan5233

    authors: Scharschmidt TC

    更新日期:2017-06-14 00:00:00

  • Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.

    abstract::Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2, or PDCD10 Disease onset is earlier and more severe in individuals with PDCD10 mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kin...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaw3521

    authors: Tang AT,Sullivan KR,Hong CC,Goddard LM,Mahadevan A,Ren A,Pardo H,Peiper A,Griffin E,Tanes C,Mattei LM,Yang J,Li L,Mericko-Ishizuka P,Shen L,Hobson N,Girard R,Lightle R,Moore T,Shenkar R,Polster SP,Roedel CJ,Li

    更新日期:2019-11-27 00:00:00

  • Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants.

    abstract::Troublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development of cell-based therapies for Parkinson's disease. The mechanisms underlying these dyskinesias are not well understood, and i...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000976

    authors: Politis M,Wu K,Loane C,Quinn NP,Brooks DJ,Rehncrona S,Bjorklund A,Lindvall O,Piccini P

    更新日期:2010-06-30 00:00:00

  • Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment.

    abstract::Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combinat...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aav7816

    authors: Zemek RM,De Jong E,Chin WL,Schuster IS,Fear VS,Casey TH,Forbes C,Dart SJ,Leslie C,Zaitouny A,Small M,Boon L,Forrest ARR,Muiri DO,Degli-Esposti MA,Millward MJ,Nowak AK,Lassmann T,Bosco A,Lake RA,Lesterhuis WJ

    更新日期:2019-07-17 00:00:00

  • Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates.

    abstract::Nonalcoholic fatty liver disease (NAFLD) is estimated to affect up to one-third of the general population, and new therapies are urgently required. Our laboratory previously developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglyceri...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aay0284

    authors: Goedeke L,Peng L,Montalvo-Romeral V,Butrico GM,Dufour S,Zhang XM,Perry RJ,Cline GW,Kievit P,Chng K,Petersen KF,Shulman GI

    更新日期:2019-10-02 00:00:00

  • Advancing translational research collaborations.

    abstract::In February 2010, the U.S. National Institutes of Health (NIH) sponsored a national Clinical and Translational Science Awards forum titled "Promoting Efficient and Effective Collaborations among Academia, Government and Industry." This forum brought together a broad set of stakeholders who were charged with developing...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3001636

    authors: Portilla LM,Evans G,Eng B,Fadem TJ

    更新日期:2010-12-22 00:00:00