Proteases: Nature’s Destroyers and the Drugs that Stop Them

Abstract

Proteases are found in all life forms and regulate many cellular pathways. Proteases have been proven as viable drug targets. This paper reviews the mechanism of hydrolysis of the amino acid based aspartic, cysteine, serine and threonine proteases and will also highlight the current anti protease therapeutics in the clinic. the oxygen of the carbonyl drive the cleavage of the peptide bond, which abstracts hydrogen from the general base. Water then releases the second half of the product from the active site residue. The oxyanion hole generated during the transition state is stabilized through hydrogen bonding with amino groups of the backbone. The role of the oxyanion hole is not fully understood [18]. While the chemistry of the mechanism of hydrolysis is similar for serine, aspartic, cysteine and threonine proteases, the amino acids involved in catalysis are what define the various classes. The different classes of proteases are discussed below. Serine ProteasesSerine proteases [19][20][21] use an active site serine to hydrolyze a peptide bond. The other amino acids involved in catalysis vary between the different serine protease groups. The Ser-His-Asp triad can be replaced with Ser-His-Glu, Ser-His-His or Ser-Lys depending on the family of serine protease [20,21]. The serine proteases are categorized by tertiary structures into the super families of the trypsin-like or subtilisin-like [2,19,20]. Examples of the trypsin-like serine proteases, the larger of the super families, are trypsin, chymotrypsin, thrombin, factor IX a, and factor Xa [2,19,20]. Interestingly, some cysteine proteases adopt the trypsin-like structure [22]. Examples of the subtilisin-like serine proteases are proteinase K and thermitase [2,19,20]. Proteases: Nature's Destroyers and the Drugs that Stop Them 3/11Copyright: ©2015 Veltri Citation: Veltri CA (2015) Proteases: Nature's Destroyers and the Drugs that Stop Them. Pharm Pharmacol Int J 2(6): 00044. DOI: 10.15406/ ppij.2015.02.00044Along with tertiary structure, serine proteases are designed against the nature of the P 1 residue recognized by the protease types. The trypsin-like proteases cleave positively charged residues (Lys or Arg are preferred at P 1 ), elastase-like proteases prefer small hydrophobic residues (Ala or Val are preferred at P 1 ) while chymotrypsin-like proteases prefer large hydrophobic residues (Phe, Tyr, or Leu) [2,19,20]. Aspartic ProteasesAspartic proteases [19,[23][24][25][26] use two aspartic acid residues to hydrolyze a peptide bond. These proteases are categorized into the super families of pepsin-like or viral retropepsin-like due to the tertiary structure [23,24,26,27]. The pepsin-like include pepsin, cathepsin D and chymosin [23,27]. The viral retropepsinlike include the retro pepsins of the immune viruses HIV, FIV and SIV [24,26].Aspartic proteases are unique in the fact they do not have a His residue in their active site. The general acid-base mechanism proposed for peptide hydrolysis involves two Asp residues and uses water to attack the targe...