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Research has been conducted on the hepatitis A virus 3C enzyme. The synthesis of the ketone-containing glutamine compounds has been carried out to test for their inhibition against hepatitis A virus 3C proteinase and the results are reported.

Research has been conducted on the hepatitis A virus 3C cysteine proteinase. The interaction of this proteinase with threonine and serine beta-lactones has been investigated and different inhibitory modes have been observed.

X-ray crystallography was used to examine the molecular structures of three phosphorus-containing peptides that act as inhibitors of aspartyl proteinases that are attached to penicillopepsin. These enzyme inhibitors were intended to imitate the tetrahedral transition-state intermediate observed during aspartic proteinase catalysis. A neutral charge was designated to Asp213 of penicillopepsin due to the hydrogen bonding between its carboxyl group and the pro-R oxygen atom. Similarly, a partial negative charge was assigned to Asp33 of the aspartic proteinase due to a smaller hydrogen bond between the amino acid and the pro-S oxygen atom of the phosphonate inhibitors.

Prion diseases in mammals are caused by a conformational transition of the cellular prion protein from its native conformation (PrPC) to a pathological isoform called "prion protein scrapie" (PrPSc). A molecular level of understanding of this conformational transition will be helpful in unveiling the disease etiology. Experimental structural biological techniques (NMR and X‐ray crystallography) have been used to unravel the atomic level structural information for the prion and its binding partners. More than one hundred three‐dimensional structures of the mammalian prions have been deposited in the protein databank. Structural studies on the prion protein and its structural transitions will deepen our understanding of the molecular basis of prion pathogenesis and will provide valuable guidance for future structure‐based drug discovery endeavors. [ABSTRACT FROM AUTHOR]

An additivity-based sequence to reactivity algorithm for the interaction of members of the Kazal family of protein inhibitors with six selected serine proteinases is described. Ten consensus variable contact positions in the inhibitor were identified, and the 19 possible variants at each of these positions were expressed. The free energies of interaction of these variants and the wild type were measured. For an additive system, this data set allows for the calculation of all possible sequences, subject to some restrictions. The algorithm was extensively tested. It is exceptionally fast so that all possible sequences can be predicted. The strongest, the most specific possible, and the least specific inhibitors were designed, and an evolutionary problem was solved.

The three-dimensional structures of the inactive protein precursors (zymogens) of the serine, cysteine, aspartic, and metalloprotease classes of proteolytic enzymes are known. Comparisons of these structures with those of the mature, active proteases reveal that, in general, the preformed, active conformations of the residues involved in catalysis are rendered sterically inaccessible to substrates by the residues of the zymogens' N-terminal extensions or prosegments. The prosegments interact in nonsubstrate-like fashions with the residues of the active sites in most of the cases. The gastric aspartic proteases have a well-characterized zymogen conversion pathway. Structures of human progastricsin, the inactive intermediate 2, and active human pepsin are known and have been used to define the conversion pathway. The structure of the zymogen precursor of plasmepsin II, the malarial aspartic protease, shows a new twist on the mode of inactivation used by the gastric zymogens. The prosegment of proplasmepsin disrupts the active conformation of the two catalytic aspartic acid residues by inducing a major reorientation of the two domains of the mature protease. The picornaviral 2A and 3C proteases have a chymotrypsin-like tertiary structure but with a cysteine nucleophile. These enzymes cleave themselves from the viral polyprotein in cis (intramolecular cleavage) and carry out trans cleavages of other scissile peptides important for the virus life cycle. Although the structure of the precursor viral polyprotein is unknown, it probably resembles the organization of the proenzymes of the bacterial serine proteases, subtilisin, and [Alpha]-lytic protease. Cleavage of the prosegment is known to occur in cis for these precursor molecules.