Вирустық инфекцияларды емдеуге қолданылатын препараттар

the drugs used to treat viral infections

In biology and biochemistry, protease inhibitors, or antiproteases, are molecules that inhibit the function of proteases (enzymes that aid the breakdown of proteins). Many naturally occurring protease inhibitors are proteins. In medicine, protease inhibitor is often used interchangeably with alpha 1 antitrypsin (A1AT, which is abbreviated PI for this reason). A1AT is indeed the protease inhibitor most often involved in disease, namely in alpha 1 antitrypsin deficiency.

Protease inhibitors may be classified either by the type of protease they inhibit, or by their mechanism of action. In 2004 Rawlings and colleagues introduced a classification of protease inhibitors based on similarities detectable at the level of amino acid sequence. This classification initially identified 48 families of inhibitors that could be grouped into 26 related superfamily (or clans) by their structure. According to the MEROPS database there are now 81 families of inhibitors. These families are named with an I followed by a number, for example, I14 contains hirudin like inhibitors.

This is a family of protease suicide inhibitors called the serpins. It contains inhibitors of multiple cysteine and serine protease families. Their mechanism of action relies on undergoing a large conformational change which inactivates their target's catalytic triad.

Proteinase propeptide inhibitors (sometimes referred to as activation peptides) are responsible for the modulation of folding and activity of the peptidase pro enzyme or zymogen. The pro segment docks into the enzyme, shielding the substrate binding site, thereby promoting inhibition of the enzyme. Several such propeptides share a similar topology, despite often low sequence identities. The propeptide region has an open sandwich antiparallel alpha/antiparallel beta fold, with two alpha helices and four beta strands with a (beta/alpha/beta)x2 topology. The peptidase inhibitor I9 family contains the propeptide domain at the N terminus of peptidases belonging to MEROPS family S8A, subtilisins. The propeptide is removed by proteolytic cleavage; removal activating the enzyme.

This family includes both microviridins and marinostatins. It seems likely that in both cases it is the C terminus which becomes the active inhibitor after post translational modifications of the full length, pre peptide. It is the ester linkages within the key, 12 residue region that circularise the molecule giving it its inhibitory conformation.

This family includes PinA, which inhibits the endopeptidase La. It binds to the La homotetramer but does not interfere with the ATP binding site or the active site of La.

The inhibitor I29 domain, which belongs to MEROPS peptidase inhibitor family I29, is found at the N terminus of a variety of peptidase precursors that belong to MEROPS peptidase subfamily C1A; these include cathepsin L, papain, and procaricain. It forms an alpha helical domain that runs through the substrate binding site, preventing access. Removal of this region by proteolytic cleavage results in activation of the enzyme. This domain is also found, in one or more copies, in a variety of cysteine peptidase inhibitors such as salarin.

The saccharopepsin inhibitor I34 is highly specific for the aspartic peptidase saccharopepsin. In the absence of saccharopepsin it is largely unstructured, but in its presence, the inhibitor undergoes a conformational change forming an almost perfect alpha helix from Asn2 to Met32 in the active site cleft of the peptidase.

The peptidase inhibitor family I36 domain is only found in a small number of proteins restricted to Streptomyces species. All have four conserved cysteines that probably form two disulphide bonds. One of these proteins from Streptomyces nigrescens, is the well characterised metalloproteinase inhibitor SMPI. The structure of SMPI has been determined. It has 102 amino acid residues with two disulphide bridges and specifically inhibits metalloproteinases such as thermolysin, which belongs to MEROPS peptidase family M4. SMPI is composed of two beta sheets, each consisting of four antiparallel beta strands. The structure can be considered as two Greek key motifs with 2 fold internal symmetry, a Greek key beta barrel. One unique structural feature found in SMPI is in its extension between the first and second strands of the second Greek key motif which is known to be involved in the inhibitory activity of SMPI. In the absence of sequence similarity, the SMPI structure shows clear similarity to both domains of the eye lens crystallins, both domains of the calcium sensor protein S, as well as the single domain yeast killer toxin. The yeast killer toxin structure was thought to be a precursor of the two domain beta gamma crystallin proteins, because of its structural similarity to each domain of the beta gamma crystallins. SMPI thus provides another example of a single domain protein structure that corresponds to the ancestral fold from which the two domain proteins in the beta gamma crystallin superfamily are believed to have evolved.

Inhibitor family I42 includes chagasin, a reversible inhibitor of papain like cysteine proteases. Chagasin has a beta barrel structure, which is a unique variant of the immunoglobulin fold with homology to human CD8alpha.

Inhibitor family I48 includes clitocypin, which binds and inhibits cysteine proteinases. It has no similarity to any other known cysteine proteinase inhibitors but bears some similarity to a lectin like family of proteins from mushrooms.

Members of this family are the peptidase inhibitor madanin proteins. These proteins were isolated from tick saliva.

Bromelain inhibitor VI, in the Inhibitor I67 family, is a double chain inhibitor consisting of an 11 residue and a 41 residue chain.

The Carboxypeptidase inhibitor I68 family represents a family of tick carboxypetidase inhibitors.

The peptidase inhibitor I78 family includes Aspergillus elastase inhibitor.