In recent years, the demand for new antiviral strategies has increased markedly. There are many contributing factors to this increased demand, including the ever-increasing prevalence of chronic ...viral infections such as HIV and hepatitis B and C, and the emergence of new viruses such as the SARS coronavirus. The potential danger of haemorrhagic fever viruses and eradicated viruses such as variola virus being used as bioterrorist weapons has also increased the profile of antiviral drug discovery. Here, the virus infections for which antiviral therapy is needed and the compounds that are available, or are being developed, for the treatment of these infections are described.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Twenty years following the description of the broad-spectrum antiviral activity of S-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (S)-HPMPA De Clercq E, Holý A, Rosenberg I, Sakuma T, Balzarini J, ...Maudgal PC. A novel selective broad-spectrum anti-DNA virus agent. Nature 1986;323:464–7, the acyclic nucleoside phosphonates have acquired a prominent therapeutic position: (i) cidofovir in the treatment of papilloma-, herpes-, adeno- and poxvirus infections, (ii) adefovir in the treatment of chronic hepatitis B virus (HBV) infections, and (iii) tenofovir in the treatment of human immunodeficiency virus (HIV) infections (AIDS). Although formally approved only for the treatment of human cytomegalovirus (HCMV) retinitis in AIDS patients, cidofovir has been used successfully in the treatment of various other DNA virus infections, particularly human papilloma virus (HPV)-associated lesions. Adefovir dipivoxil has become a standard therapy for HBV infections, especially when resistant to lamivudine. Tenofovir disoproxil fumarate (TDF) is the corner stone of the triple-drug (TDF, emtricitabine, and efavirenz) combination therapy for AIDS, and TDF, alone or combined with emtricitabine may in the future evolve to the standard therapy of hepatitis B. Guided by the results obtained with tenofovir in the prevention of parenteral, intravaginal and perinatal infections with simian immunodeficiency virus in monkeys, and the safety profile gathered with TDF in humans with AIDS over the past 5 years since TDF was licensed for clinical use, it should be further pursued for the pre- and post-exposure prophylaxis of HIV infections in humans. Meanwhile, new classes of both acyclic (i.e. PMPO-DAPy, PMEO-DAPy, HPMPO-DAPy) and cyclic nucleoside phosphonates (i.e. PMDTA, PMDTT, GS9148) have been accredited with an antiviral potency and selectivity similar to those of cidofovir, adefovir and/or tenofovir.
Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse ...transcriptase inhibitors (NRTIs): i.e., zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine (-)FTC, tenofovir (PMPA) disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine (MKC- 442); and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease step, various other events in the HIV replicative cycle are potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polyoxometalates, zintevir, negatively charged albumins, cosalane analogues); (ii ) viral entry, through blockade of the viral coreceptors CXCR4 and CCR5 bicyclams (i.e. AMD3100), polyphemusins (T22), TAK-779, MIP-1α LD78β isoform; (iii) virus-cell fusion, through binding to the viral glycoprotein gp41 T-20 (DP-178), T-1249 (DP-107), siamycins, betulinic acid derivatives; (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents 2,2 ’ - dithiobisbenzamides (DIBAs), azadicarbonamide (ADA) and NCp7 peptide mimics; (v) proviral DNA integration, through integrase inhibitors such as L-chicoric acid and diketo acids (i.e. L-731,988); (vi ) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (fluoroquinolone K-12, Streptomyces product EM2487, temacrazine, CGP64222). Also, in recent years new NRTIs, NNRTIs and PIs have been developed that possess respectively improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides of d4T), or increased activity against NNRTI-resistant HIV strains second generation NNRTIs, such as capravirine and the novel quinoxaline, quinazolinone, phenylethylthiazolylthiourea (PETT) and emivirine (MKC-442) analogues, or, as in the case of PIs, a different, non-peptidic scaffold i.e. cyclic urea (DMP 450), 4-hydroxy-2-pyrone (tipranavir). Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating from cellfree enzymatic assays to the mode of action of these agents in intact cells. A number of compounds (i.e. zintevir and L-chicoric acid, on the one hand; and CGP64222 on the other hand) have recently been found to interact with virus-cell binding and viral entry in contrast to their proposed modes of action targeted at the integrase and transactivation process, respectively.
This study examined the family emotional climate as assessed by Five Minute Speech Samples and the relation with parenting stress and parenting behaviors among parents of children (6–17 years, 64.7% ...boys) with autism spectrum disorder, cerebral palsy, Down syndrome, and without any known disability (
n
= 447). The large majority of parents (79%) showed low levels of Expressed Emotion, an indicator of a positive family climate. In all groups, more Emotional Over-involvement, more Criticism and fewer expressions of Warmth were associated with higher levels of parenting stress. Across groups, Emotional Over-involvement was related to more autonomy-supportive parenting, Criticism to more psychologically controlling and overreactive parenting, and Warmth was associated with more responsive and less psychologically controlling and overreactive parenting.
Curcumin bioconjugates, viz. di-
O-tryptophanylphenylalanine curcumin (
2), di-
O-decanoyl curcumin (
3), di-
O-pamitoyl curcumin (
4), di-
O-bis-(γ,γ)folyl curcumin (
6), C
4-ethyl-
O-γ-folyl ...curcumin (
8) and 4-
O-ethyl-
O-γ-folyl curcumin (
10) have been synthesized and tested for their antibacterial and antiviral activities. The conjugates
2,
3,
4,
6 and
8 have shown very promising antibacterial activity with MIC ranging between 0.09 and 0.67
μM against Gram-positive cocci and Gram-negative bacilli. Further, the conjugates
2,
3,
6,
8 and
10 have been screened for their antiviral activities against HSV, VSV, FIPV, PIV-3, RSV and FHV and the molecules
2 and
3 have shown good results with EC
50 0.011
μM and 0.029
μM against VSV and FIPV/FHV, respectively. However, the molecules did not show expected results against HIV-1 III
B and ROD strains in MTT assay.
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Correct identification of the source population of an invasive species is a prerequisite for testing hypotheses concerning the factors responsible for biological invasions. The native area of ...invasive species may be large, poorly known and/or genetically structured. Because the actual source population may not have been sampled, studies based on molecular markers may generate incorrect conclusions about the origin of introduced populations. In this study, we characterized the genetic structure of the invasive ladybird Harmonia axyridis in its native area using various population genetic statistics and methods. We found that native area of H. axyridis most probably consisted of two geographically distinct genetic clusters located in eastern and western Asia. We then performed approximate Bayesian computation (ABC) analyses on controlled simulated microsatellite data sets to evaluate (i) the risk of selecting incorrect introduction scenarios, including admixture between sources, when the populations of the native area are genetically structured and sampling is incomplete and (ii) the ability of ABC analysis to minimize such risks by explicitly including unsampled populations in the scenarios compared. Finally, we performed additional ABC analyses on real microsatellite data sets to retrace the origin of biocontrol and invasive populations of H. axyridis, taking into account the possibility that the structured native area may have been incompletely sampled. We found that the invasive population in eastern North America, which has served as the bridgehead for worldwide invasion by H. axyridis, was probably formed by an admixture between the eastern and western native clusters. This admixture may have facilitated adaptation of the bridgehead population.
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