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Biomedical subjects

P S Miller

Publications and source records attributed to P S Miller.

At least 19 recordsLinked to original sources
PubMed1995

Inhibition of herpes simplex virus replication by antisense oligo-2'-O-methylribonucleoside methylphosphonates.

Antisense oligonucleoside methylphosphonates complementary to the 12 nucleotides found at the intron/exon junction of the splice acceptor site of herpes simplex virus type 1 (HSV-1) immediate early mRNAs 4 and 5 were synthesized. The methylphosphonate oligomers contained either 2'-deoxyribose nucleosides, d-OMPs, or 2'O-methylribose nucleosides, mr-OMPs. At 37 degrees C, the affinity of the mr-OMP for a complementary 12-mer RNA target was approximately four times higher than that of the corresponding d-OMP as measured by a constant activity gel electrophoresis mobility shift assay. An mr-OMP whose sequence contained two mismatched bases did not bind to the RNA target under these conditions. The mr-OMP also showed improved ability to inhibit HSV-1 replication in HSV-1 infected Vero cells in culture. Thus the IC50 of the mr-OMP was five times less than that of the d-OMP. No inhibition was observed by the mismatched mr-OMP, and no inhibition of herpes simplex virus type 2 (HSV-2) replication was observed with any of the oligomers. These results demonstrate a direct correlation between oligomer binding affinity and antisense activity in cell culture and suggest that oligo-2'-O-methylribonucleoside methylphosphonates are promising candidates for development of effective antisense reagents.

Animals↗
PubMed1994

Interactions of oligonucleotide analogs containing methylphosphonate internucleotide linkages and 2'-O-methylribonucleosides.

The interactions of oligonucleotide analogs, 12-mers, which contain deoxyribo- or 2'-O-methylribose sugars and methylphosphonate internucleotide linkages with complementary 12-mer DNA and RNA targets and the effect of chirality of the methylphosphonate linkage on oligomer-target interactions was studied. Oligomers containing a single Rp or Sp methylphosphonate linkage (type 1) or oligomers containing a single phosphodiester linkage at the 5'-end followed by 10 contiguous methylphosphonate linkages of random chirality (type 2) were prepared. The deoxyribo- and 2'-O-methylribo- type 1 12-mers formed stable duplexes with both the RNA and DNA as determined by UV melting experiments. The melting temperatures, Tms, of the 2'-O-methylribo-12-mer/RNA duplexes (49-53 degrees C) were higher than those of the deoxyribo-12mer/RNA duplexes (31-36 degrees C). The Tms of the duplexes formed by the Rp isomers of these oligomers were approximately 3-5 degrees C higher than those formed by the corresponding Sp isomers. The deoxyribo type 2 12-mer formed a stable duplex, Tm 34 degrees C, with the DNA target and a much less stable duplex with the RNA target, Tm < 5 degrees C. In contrast, the 2'-O-methylribo type 2 12-mer formed a stable duplex with the RNA target, Tm 20 degrees C, and a duplex of lower stability with the DNA target, Tm < 5 degrees C. These results show that the previously observed greater stability of oligo-2'-O-methylribonucleotide/RNA duplexes versus oligodeoxyribonucleotide/RNA duplexes extends to oligomers containing methylphosphonate linkages and that the configuration of the methylphosphonate linkage strongly influences the stability of the duplexes.

Adenosine↗
PubMed1994

Effect of target structure on cross-linking by psoralen-derivatized oligonucleoside methylphosphonates.

A series of psoralen-derivatized oligodeoxyribonucleoside methylphosphonates were examined for their abilities to cross-link to DNA and RNA oligonucleotide targets. These targets were designed to have either a random coil or a hairpin structure in solution. The methylphosphonate oligomers cross-linked with approximately the same rates to the random coil DNA and RNA targets, although the extent of cross-linking to the DNA target was higher than that to the RNA target. For a given methylphosphonate sequence, cross-linking decreased as the temperature increased, and this behavior paralleled the interaction of the oligomer with the target as determined by ultraviolet melting experiments. The oligomers also cross-linked efficiently with the DNA hairpin target, but little or no cross-linking was observed with the RNA hairpin. In the case of these hairpin targets, the extent of cross-linking was dependent upon the location of the oligomer binding site relative to the stem and loop regions of the hairpin. The lack of reactivity with the RNA hairpin may be due to the high stability of the stem of this target versus that in the DNA target and the relatively lower efficiency of binding of the methylphosphonates to RNA versus DNA targets. The sequences of the oligomers are complementary to vesicular stomatitis virus M-protein mRNA. One of the oligomers was tested, and was found to cross-link at 20 degrees C to VSV N-mRNA to approximately the same extent as observed for cross-linking with the random coil RNA target, suggesting that the mRNA binding site for the oligomer most likely is in a somewhat open conformation.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

Rare alleles, MHC and captive breeding.

In recent years, more detailed genetic information has become available for individuals of endangered species in captive breeding programs. There have been suggestions that this information be used to identify rare alleles, particularly those at the MHC, that can be subsequently selected for captive breeding programs. First, we summarize the current information on the MHC relevant to conservation genetics, so that such a possible breeding program is seen in a proper perspective. For example, very few specific alleles at the MHC have been identified as selectively advantageous, even though there has been substantial effort to find such alleles in humans and a few other organisms. Further, many of the balancing selection models suggested for MHC variation are based on heterozygotes in general having a higher fitness than homozygotes and not on specific selectively advantageous alleles. Because there is no detailed data on MHC variability in captive populations, we used transferrin data in Przewalski's horses to evaluate a breeding program to select for rare alleles. In this species, one individual, 1060, has been identified to have the transferrin allele J. We determine the effect on founder contribution of multiply mating 1060 to increase the number of copies of this allele. Since there were 485 individuals in the population at this time, this extra mating had little detrimental effect on the distribution of founder contributions and the number of founder equivalents. We then selected 65, an ancestor of 1060, which had a high likelihood of being the individual that passed on the J allele in the lineage of 1060. We examined the effect of increasing the number of copies of alleles of 65 at a time when the population had only 22 other individuals. In this case, even though the founder contributions were changed more, there was also little effect on the founder contributions and the number of founder equivalents. Overall, it appears that selection that results in a limited change in the number of copies of rare alleles may not always have an overall detrimental effect. However, because other pedigrees may have very different properties, it is essential to perform a detailed pedigree analysis of any such selective breeding program to determine its effect before such a selection program is implemented.

Alleles↗
PubMed1994

Interactions of psoralen-derivatized oligodeoxyribonucleoside methylphosphonates with vesicular stomatitis virus messenger RNA.

The ability of oligonucleotides to interact selectively with their targets is an important consideration in the design of antisense oligonucleotides. This is especially important in the case of antisense oligomers, such as psoralen-derivatized oligomers, which can irreversibly bind to their targets. We have studied the interactions of a series of psoralen-derivatized antisense oligonucleoside methylphosphonates with the mRNAs of vesicular stomatitis virus (VSV), mRNAs that have a high degree of sequence homology. Cross-linking reactions were carried out under conditions of low ionic strength in order to reduce mRNA secondary structure. A 12-mer, whose sequence was complementary to VSV M-mRNA and partially complementary to sequences found in N, NS, and G mRNA cross-linked extensively to N-message. On the other hand, 16-mers whose sequences were uniquely complementary to binding sites on N- or M-mRNA specifically and efficiently cross-linked to their targeted mRNAs over the temperature range 0 degree to 37 degrees C. A reverse transcriptase-catalyzed primer extension assay was used to show that one of the N-specific oligomers cross-linked at the expected site on N-mRNA and to estimate the extent of cross-linking. The results demonstrate that psoralen-derivatized oligonucleoside methylphosphonates can cross-link in a sequence-specific manner if the sequences of these oligomers are chosen carefully so as to avoid extensive partial complementarity with other mRNA sequences.

Animals↗
PubMed1994

Properties of exonuclease-resistant, psoralen-conjugated oligodeoxyribonucleotides in vitro and in cell culture.

We have prepared oligodeoxyribonucleotides that are modified at the 3'-terminal with N4-(4-aminobutyl)deoxycytidine and derivatized at the 5'-end with a 4'-([N-(aminoethyl)amino]methyl)-4,5',8-trimethylpsoralen, (ae)AMT, and whose sequences are complementary to vesicular stomatitis virus (VSV), N-protein mRNA, (ae)AMT-II, or VSV M-protein mRNA, (ae)AMT-III. (ae)AMT-II cross-links exclusively to VSV N-mRNA when a mixture of the oligomer and poly(A+) RNA from VSV-infected cells is irradiated in vitro with long wavelength UV light at either 20 degrees or 37 degrees C. N4-(4-Aminobutyl)deoxycytidine at the 3'-end of (ae)AMT-II does not appear to affect the binding or cross-linking of the oligomer to its target RNA. Oligomer (ae)AMT-II is completely resistant to hydrolysis by the 3'-5'-exonuclease activity found in fetal calf serum whereas a similar oligomer, (ae)AMT-I, which contains a 3'-terminal deoxycytidine, is hydrolyzed within 30 min when incubated at 37 degrees C. Intact (ae)AMT-II was found in both the cell lysate and cell culture medium after 12 hr of incubation with mouse L-cells along with d-(ae)AMTpT, which appears to result from endonuclease degradation of the oligomer. In contrast no intact (ae)AMT-I was found in either the cell lysate or the culture medium after 1 hr incubation. Although 10 microM (ae)AMT-II had no effect on VSV-protein synthesis in either unirradiated or UV-irradiated VSV-infected mouse L-cells, 10 microM (ae)AMT-III inhibited VSV protein synthesis 30% in irradiated cells. These results show that introduction of a N4-(4-aminobutyl)deoxycytidine at the 3'-end of an oligodeoxyribonucleotide significantly increases the resistance of the oligomer to degradation by 3'-5'-exonucleases but does not interfere with its ability to bind selectively to complementary RNA. Further derivatization with psoralen creates an oligomer that can be triggered to cross-link with RNA in a sequence-specific manner, is taken up intact by mammalian cells in culture, and exhibits biological activity. In combination, these two modifications endow the oligodeoxyribonucleotide with novel properties that could be exploited in the design of antisense or antigene reagents for use in controlling gene expression in mammalian cells.

Animals↗
PubMed1994

Synergistic antiviral activities of oligonucleoside methylphosphonates complementary to herpes simplex virus type 1 immediate-early mRNAs 4, 5, and 1.

An oligonucleoside methylphosphonate (ONMP) complementary to the splice acceptor site of immediate-early (IE) pre-mRNAs 4 and 5 (IE4,5SA) inhibits herpes simplex virus type 1 (HSV-1) growth in vitro and in infected animals. The antiviral effect appears to be due to inhibition of IE pre-mRNA 4 and 5 splicing and/or IE4 gene expression (M. Kulka, M. Wachsman, S. Miura, R. Fishelevich, P. S. Miller, P. O. P. Ts'o, and L. Aurelian, Antiviral Res. 20:115-130, 1993). We describe the potentiation of antiviral activity when we targeted two IE genes with different ONMPs. A psoralen derivative of an ONMP complementary to the IE mRNA 1 (IE1) translation initiation site (IE1TI) covalently bound a 2.8-kb transcript that hybridized with a 20-base oligonucleotide complementary to the 5' leader sequence of IE1 but not a 20-base oligonucleotide complementary to the first intron of IE1. IE1TI inhibited IE1 gene expression and virus replication in cells infected with HSV-1 in vitro. Inhibition was specific because it was not observed with oligomers mutated in two (IE1TImu1) or four (IE1TImu2) central residues or in cells infected with an IE1 deletion mutant (HSV-1 dl1403). IE1TI potentiated the antiviral activity of IE4,5SA (synergistic effect), while potentiation was not observed when IE4,5SA was mixed with IE1TImu1. A similar synergistic effect was seen when IE1TI was mixed with an ONMP complementary to the translation initiation site of IE mRNA 4 but not with an ONMP complementary to the translation initiation site of IE mRNA 5. These findings suggest that synergistic antiviral activity is mediated by targeting at least two IE genes (IE1 and IE4).

Animals↗
PubMed1994

Bioavailability of zinc from inorganic and organic sources for pigs fed corn-soybean meal diets.

Two experiments were conducted with pigs 1) to determine the effect of supplemental Zn on growth performance, bone Zn, and plasma Zn in pigs fed Zn-unsupplemented, corn-soybean meal diets and 2) to assess bioavailability of Zn from inorganic and organic Zn sources. In both experiments, weanling pigs were fed a diet with no supplemental Zn for 5 wk to deplete their Zn stores. In Exp. 1, 192 pigs were fed a corn-soybean meal diet (growing diet, 32 mg/kg of Zn; finishing diet, 27 mg/kg of Zn) supplemented with feed-grade ZnSO4.H2O to provide 0, 5, 10, 20, 40, and 80 mg/kg of supplemental Zn. Supplemental Zn did not affect weight gain, feed intake, or gain/feed during either the growing or the finishing period (P > .05). However, bone and plasma Zn concentrations increased linearly (P < .01) in response to supplemental Zn at dietary Zn levels between 27 mg/kg (basal) and 47 mg/kg (breakpoint). In Exp. 2, three levels of supplemental Zn from ZnSO4.H2O (0, 7.5, and 15 mg/kg of supplemental Zn) were used to construct a standard curve (metacarpal, coccygeal vertebrae, and plasma Zn concentrations regressed on supplemental Zn intake; R2 = .93, .89, and .82, respectively). From the standard curve, the bone and plasma Zn concentrations obtained from pigs fed 15 mg/kg of supplemental Zn from ZnO and 7.5 mg/kg of supplemental Zn from Zn-methionine (ZnMET) and Zn-lysine (ZnLYS) were used to calculate bioavailable Zn via multiple linear regression, slope-ratio analysis. The estimates of Zn bioavailability differed depending on which variable was used. Overall trends indicated the following rankings: ZnSO4.H2O > ZnMet > ZnO > ZnLys.

Animal Feed↗
PubMed1994

Temporal response of rabbits to beta-adrenergic agonist feeding: tissue weight, calpains and calpastatin activities, and nucleic acid and protein concentrations.

Forty-eight crossbred rabbits were used in three replications of a 2 x 4 factorial arrangement to investigate the short-term responses of tissue accretion, calpains and calpastatin activity, and nucleic acid and protein concentrations to beta-adrenergic agonist (BAA) feeding. Rabbits were fed a 17% CP diet with or without 7 ppm of L644,969 and slaughtered after 1, 4, 8, or 16 d of treatment. Empty body dressing percentage and biceps femoris weight (as a percentage of empty body weight [EBW]) were significantly higher in the treated rabbits than in the controls after 16 d of treatment. Heart and liver weights (as a percentage of EBW) were higher (P < .05) after 1 d and liver weight (as a percentage of EBW) was lower (P < .05) after 16 d in treated vs controls. Except for an elevation of skeletal muscle m-calpain after 16 d, BAA-supplementation did not affect the calpain-calpastatin system. Muscle RNA concentrations and RNA:DNA ratios were higher (P < .05) in treated rabbits after 1 d and remained higher thereafter. Protein:RNA ratios were lower (P < .01) in treated than in control rabbits after 4 d and remained lower throughout the trial. Muscle DNA content was lower after 4 d and higher after 16 d; RNA content was higher after 4, 8, and 16 d; and protein content was higher after 16 d in treated vs control rabbits. Liver nucleic acid and protein concentrations were not affected by BAA treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1994

Diet preference and meal patterns of weanling pigs offered diets containing either spray-dried porcine plasma or dried skim milk.

Preference tests and meal pattern analyses were conducted to examine the feed intake response of weanling pigs to spray-dried porcine plasma (SDPP). In Exp. 1, 36 weanling pigs (mean +/- SD; 6.2 +/- .8 kg and 26 d of age) were allowed to choose between a SDPP diet (8.5% SDPP, 20% dried whey, 10% lactose, and .13% DL-methionine) and a dried skim milk (DSM) diet (20% each of DSM and dried whey) throughout 21 d postweaning. Twenty-eight pigs preferred the SDPP diet and seven pigs preferred the DSM diet. Preference for SDPP became apparent by d 2 (60% of total feed consumption) and increased (P < .01) to d 21 (71% of total feed consumption). Average daily feed consumption was 371 and 172 g for the SDPP and DSM diets, respectively (P < .01). The meal patterns of 16 weanling pigs (mean +/- SD; 7.2 +/- .3 kg and 26 d of age) offered either the SDPP or the DSM diet were examined in Exp. 2. On d 3, 7, and 14 postweaning, feeding behavior was observed continuously for 18 h (0600 to 2400). Time spent consuming feed and time between periods of feeding were recorded. Although the difference was not significant, pigs fed the SDPP diet consumed 27 and 6% (P = .38) more feed than pigs fed the DSM diet during the first 7 d and during the entire 21-d period, respectively. This difference was reflected in increased (P < .05) rate of feed consumption on d 3 and 7. Diet had no effect (P > .10) on meal size, the number of meals, or the percentage of time spent consuming feed. Weanling pigs prefer diets containing SDPP to those containing DSM, and the increased consumption of diets containing SDPP may be due to greater palatability.

Analysis of Variance↗
PubMed1994

The effect of protein intake on boar libido, semen characteristics, and plasma hormone concentrations.

To determine the effect of low protein intake on boar libido, semen characteristics, and plasma hormone concentrations, 20 crossbred boars (1 yr of age) were divided into 10 littermate pairs, and boars from within pairs were fed 44 g/kg of BW.75 per day of either a low-protein diet (7% CP) or a control diet (16% CP) with the same energy content (3.41 Mcal of ME/kg). During the first 16 wk and from wk 19 to 23, semen was collected two times per week. During wk 17 and 18, boars were subdivided within dietary treatment and semen was collected either two or seven times per week. Blood samples were collected at 12-min intervals for 6 h before and 1 h after an intravenous injection of GnRH (375 ng/kg of BW) during wk 24. All plasma samples were analyzed for LH and pooled samples were analyzed for estradiol-17 beta and testosterone. Boars with low protein intakes required more time to start ejaculation (P = .11, wk 0 through 7; P < .04, after wk 7), had a shorter duration of ejaculation (P < .09, wk 19 through 23), and had reduced semen volumes (P < .01, after wk 7) compared with boars on the control treatment. There was no interaction between dietary treatment and semen collection frequency (P > .39) for any of the semen or libido measurements. Testosterone and LH concentrations were not affected by protein intake (P > .5). However, concentration of estradiol-17 beta was greater in boars fed the control diet than in boars fed the low-protein diet (582 vs 202 pg/mL, respectively; P < .08). Estrogen concentrations in boars were negatively correlated with the time required for the boar to start ejaculating (r2 = .72). Boars with low protein intakes had reduced libido and semen volume. This reduction in libido and semen volume may be a result of a decrease in estradiol-17 beta concentration in circulation.

Amino Acids↗
PubMed1994

The effect of energy and protein intakes on boar libido, semen characteristics, and plasma hormone concentrations.

To determine the effect of energy and protein intakes on boar libido, semen characteristics, and plasma hormone concentrations, 24 crossbred boars (1 yr of age) were allotted to one of three dietary treatments. Two protein levels (7.7 and 18.1 g/d of lysine) and two energy levels (6.1 and 7.7 Mcal/d of ME) were combined to create 1) low-energy and low-protein (ep), 2) low-energy and high-protein (eP), and 3) high-energy and high-protein (EP) treatments. Semen was collected two times per week for 27 wk. During wk 28, blood samples were collected before and after a intravenous injection of GnRH (375 ng/kg of BW). The EP boars had higher (P < .01) ADG than the eP boars (373 vs 169 g), which had higher (P < .01) ADG than the ep boars (169 vs 92 g). Fewer EP and eP boars (zero of eight and two of eight, respectively) than ep boars (five of eight) consistently refused to mount the collection dummy (P < .05). During the final 20 wk of the semen-collection period, EP and eP boars had 33% longer durations of ejaculation (P < .04), had 60% greater semen and gelatinous fraction volumes (P < .03), but had 25% lower sperm concentration in their semen (P < or = .12) than ep boars. The EP boars produced 38% more sperm than the ep boars (P < .10). Baseline LH concentration, LH pulse frequency, LH pulse amplitude, testosterone concentration, and estradiol-17 beta concentrations were not affected by treatment (P > .10).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Recognition of a guanine-cytosine base pair by 8-oxoadenine.

Two oligodeoxyribonucleotides, d-CTTCTTTTTTATTTT, I(A), and d-ATTATTTTTTATTTT, II(A), where C is 5-methylcytosine and A is 8-oxoadenine, were prepared and their interactions with the duplex d-GAAGAAAAAAYAAAA/d-TTTTZTTTTTTCTTC, III.IV(Y.Z), were studied. Oligomers I(A) and II(A) each form triplexes with III.IV(G.C) at temperatures below 20 degrees C as shown by continuous variation experiments, melting experiments, and circular dichroism (CD) spectroscopy. The CD spectra of these triplexes are almost identical to those formed by I(C) and II(C), oligomers which contain cytosine in place of 8-oxoadenine. This suggests that the 8-oxoadenine-containing triplexes have conformations which are very similar to those of the cytosine-containing triplexes. The melting temperature (Tm) for dissociation of the third strand of triplex II.III.IV(A.G.C) is 22 degrees C at pH 7.0 and 8.0, whereas the Tm of the corresponding transition in triplex II.III.IV(C.G.C) decreases from 28 degrees C at pH 7.0 to 17 degrees C at pH 8.0. The pH dependence of the Tm in the latter triplex reflects the necessity of protonating the N-3 of cytosine in order for it to form two hydrogen bonds with G of the G.C base pair. It appears that the keto form of 8-oxoadenine can potentially form two hydrogen bonds with the N-7 and O-6 atoms of G of the G.C base pair, when the 8-oxoadenine is in the syn conformation and in contrast to cytosine does not require protonation of the base. Oligomer I(A) does not form triplexes with III.IV(Y.Z) when Y.Z is A.T or T.A.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗
PubMed1991

Antisense inhibition of ras p21 expression that is sensitive to a point mutation.

Many genetic disorders result from a single point mutation, and many tumor oncogenes have been found to be altered by a point mutation. The ability to inhibit selectively the expression of the mutated form of a protein without affecting its normal counterpart is central to many therapeutic strategies, since the normal protein may serve indispensable functions. Antisense oligonucleoside methylphosphonates and their psoralen derivatives directed at either normal human Ha-ras p21 or ras p21 that is mutated at a single base in codon 61 have been examined for their efficacy and specificity as inhibitors of p21 expression. Mixed cultures of cells expressing both forms of p21 were treated with the antisense oligomer complementary to the normal p21 or with the antisense oligomer complementary to the point-mutated p21. Each of the antisense oligomers specifically inhibited expression of only the form of ras p21 to which it was completely complementary and left the other form of p21 virtually unaffected.

Base Sequence↗
PubMed1991

Comparative circular dichroism and fluorescence studies of oligodeoxyribonucleotide and oligodeoxyribonucleoside methylphosphonate pyrimidine strands in duplex and triplex formation.

An analogue of the homopyrimidine oligodeoxyribonucleotide d(CT)8 has been synthesized. This analogue, d(CT)8 contains nonionic methylphosphonate internucleoside linkages. The pH-dependent conformational transitions of d(CT)8 have been studied and its ability to form duplexes and triplexes with the normal homopurine oligonucleotide d(AG)8 has also been investigated as a function of pH. Circular dichroism spectroscopy and ethidium bromide fluorescence enhancement have been used to monitor pH-dependent conformational transitions driven by the protonation of cytosine residues, and the different behavior of d(CT)8 and d(CT)8 has been compared. It was possible to form self-associated complexes by using either d(CT)8 or d(CT)8, and both compounds combined with d(AG)8 to form duplex or triplex DNA. At neutral pH, the CD spectrum of d(AG)8.d(CT)8 duplex was quite different from the CD spectrum of d(AG)8.d(CT)8 duplex, reflecting most likely a difference in conformation. The duplex to triplex transition characteristic of this DNA sequence occurred at a lower pH when d(CT)8 was substituted for d(CT)8; however, at pH 4.2, triplex containing d(CT)8 was similar in conformation to triplex containing d(CT)8. Several of these observations can be related to the alterations in electrostatic and steric interactions that occur when the negatively charged phosphodiester backbone of d(CT)8 is replaced with a nonionic methylphosphonate backbone.

Circular Dichroism↗
PubMed1991

Oligonucleoside methylphosphonates as antisense reagents.

Oligonucleoside methylphosphonates contain nonionic internucleotide bonds that resist degradation by cellular nucleases and allow the oligomers to be taken up intact by mammalian cells in culture. Antisense methylphosphonate oligomers targeted against cellular or viral mRNA initiation codon or coding regions or against precursor mRNA splice sites effectively and specifically inhibit mRNA expression in cells. The efficacy of antisense methylphosphonate oligomers can be enhanced by derivatization with functional groups that allow the oligomer to covalently cross-link with its targeted mRNA. These oligonucleotide analogs will be useful tools for studying and controlling gene expression and are also promising candidates for development as therapeutic agents.

Animals↗