Kam edhe nje lajm tjeter nga zbulimet e reja te botes shkencore qe do te tmerroje te semuret nga virusi qe shkakton vuajtjen nga SIDSA (Sindromi I Deficiences Se Arsyes).
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Legjenda:
Peptide nucleic acid (gold) readily enters DNA ’s major groove to form triple-stranded and other structures with DNA , allowing it to modify the activity of genes in new ways.
(pjesen tjeter po ua jap ne tekst format)
In addition to fomenting exciting medical research, these amazing molecules have inspired speculations relating to the origin of life on earth. Some scientists have suggested that PNAs or a very similar molecule may have formed the basis of an early kind of life at a time before proteins, DNA and RNA had evolved. Perhaps rather than creating novel life, artificial-life researchers will be re-creating our earliest ancestors.
Into the Groove
The story of PNA’s discovery begins in the early 1990s. To generate drugs with broader capabilities than antisense RNA, my colleagues Michael Egholm, Rolf H. Berg, and Ole Buchardt and I wanted to develop small molecules able to recognize
double-stranded, or duplex, DNA having specific sequences of bases—no easy task. The difficulty has to do with the structure of the familiar DNA double helix.
It is the bases—thymine (T), adenine (A), cytosine (C) and guanine (G)—that store information in DNA. (In RNA, thymine is replaced by the very similar molecule uracil, or U.) Pairs of these bases joined by hydrogen bonds form the “rungs” of the familiar DNA “ladder.” C binds with G, and A binds with T, in what is called
Watson-Crick base-pairing. A compound that binds with a stretch of double-helical DNA having a characteristic base sequence would therefore be one that acts on any gene containing that particular sequence of bases on one of its strands.
The task of recognition is relatively easy if a compound has to find a particular base sequence on single-stranded DNA or RNA. If two nucleic acid strands have complementary sequences, standard base-pairing can zip the two strands
together. Thus, if one knows the sequence of a gene—from Human Genome Project data, for instance—producing a molecule to latch onto a section of the gene in a single strand is as simple as synthesizing the complementary sequence.
In duplex DNA, however, the task of recognizing a sequence is more challenging because the atoms responsible for Watson-Crick pairing are already involved in the hydrogen bonds linking the two strands together and thus are not available for linking with another molecule. Yet cells contain numerous so-called gene-regulatory proteins that recognize sequences in duplex DNA to carry out their function of controlling gene expression. So the feat can be accomplished.
If my group could find molecules capable of the task, the molecules could potentially serve as gene-regulating drugs.
Gene expression takes place in two stages. First, in transcription, an enzyme constructs messenger RNA (mRNA), which is a strand of RNA with a copy of the base sequence of one strand in the DNA helix. A molecular machine known as a ribosome, itself made of RNA and protein, carries out the second stage, translation
of the mRNA into the protein coded by the gene. Antisense agents interfere with translation by binding to the mRNA. These compounds are typically small, chemically modified RNA or DNA molecules, designed with the appropriate
sequence to identify their mRNA target by Watson-Crick base-pairing. By binding to its mRNA, the agent may trigger enzymes to degrade the RNA or may simply interfere physically with the mRNA’s functioning.
Cells make use of proteins called transcription factors that recognize specific sequences in double-stranded DNA to control gene expression at the transcription stage. These proteins can repress a gene by obstructing the RNA polymerase
enzyme that would otherwise transcribe the DNA’s sequence into mRNA, or they can activate a gene by helping the RNA polymerase to attach to the DNA and start transcription.
Although these proteins offer a model of molecules capable of “reading” the DNA sequence from the outside of the helix, in the 1990s it was not yet possible for biochemists to start with a sequence and design a new protein to recognize
it. A gene-regulatory protein recognizes its DNA sequence by having the correct overall shape and chemical composition on its surface to bind with the sequence in the so-called major groove of the DNA, which provides access to the base pairs
that run along the center of the double helix. But the structure of the protein’s active surface depends on how its chain of amino acids folds up, a process that researchers cannot model with any accuracy.
Some progress has been made since then by taking the lead from gene-regulatory proteins that include zinc-finger domains, which are lengths of about 30 amino acids that fold around a zinc ion, forming a characteristic “finger” structure that can fit in the major groove with a few amino acids lined up with the DNA’s bases. Researchers have developed artificial proteins with zinc fingers, but in general it is still difficult to program a sequence of amino acids to match even a relatively short DNA sequence.
A discovery dating back to 1957, only four years after the discovery of the DNA double helix, provides another approach. That year Gary Felsenfeld, Alexander Rich and David Davies, all then at the National Institute of Mental Health, created triple helix structures in which a nucleic acid strand attaches itself in the major groove of a duplex nucleic acid molecule. The extra strand exploits a different kind of bonding of the base pairs T-A and C-G called Hoogsteen pairing, after Karst Hoogsteen [see box on preceding page]. Each position along the triplex thus has a triplet of bases in which a T binds to a T-A pair (T-A=T, where the “=” indicates the Hoogsteen pairing) or a C binds to a C-G unit (C-G=C). This structure, however, can form only when the extra strand is a homopyrimidine—made entirely of C and T (or U, in RNA)—because each Hoogsteen pair requires a G or an A on the strand of the double helix.
In 1987 the late Claude Hélčne, then at the National Museum of Natural History in Paris, and Peter B. Dervan of the California Institute of Technology independently demonstrated that the triple helix structure could indeed be exploited to design oligonucleotides (DNA strands about 15 nucleotides long) that read the sequence in double-stranded DNA and bind their Hoogsteen complementary target.
A Surprise Invasion
Inspired by this digital readout of the DNA double helix by groove-binding, triple helix–forming oligonucleotides, my group set out to synthesize a molecule that could do the same trick with fewer limitations. In particular, we hoped to find molecules that would not be limited to recognizing sequences made entirely of G and A. We also wanted our molecule to be neutral. The backbone of nucleic acids contains phosphate groups that carry a negative charge in solution. The repulsion caused by these negative charges on all three backbones weakens the binding of the third strand to the triplex.
We therefore decided to base the design on amide chemistry, involving the same kind of bond as links amino acids in proteins. Well-established techniques using amide, or peptide, bonds allow convenient synthesis of highly stable, neutral molecules. The peptide nucleic acid molecule that we came up with has a peptidelike backbone made of a much simpler repeating unit than the sugar and phosphate of DNA and RNA. Each unit may have a standard nucleic acid base (T, A, C or G) linked to it or bases that have been modified for special purposes. The spacing between bases along a PNA is very close to that of DNA and RNA, enabling
short PNA strands, or PNA oligomers, to form very stable duplex structures with DNA and RNA strands as well as with another PNA strand. The bases zip together with standard Watson-Crick bonding.
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