Abstract: Methods and pharmaceutical compositions which inhibit the activity of D-amino acid oxidase (DAO) are disclosed. Inhibition of DAO improves memory, learning and cognition in individuals suffering from neurodegenerative diseases such as Alzheimer's, Huntington's or Parkinson's diseases; the methods and pharmaceutical compositions which inhibit the activity of DAO also improve cognitive dysfunctions associated with aging and improve catatonic schizophrenia. Several genera of heterocycle-2-carboxylic acids are disclosed as DAO inhibitors.

Abstract: Inhibitory drug combinations targeted against a protein and first-generation, drug- resistant mutants of the protein. In a preferred embodiment, a combination of drugs that inhibits the activity of a protein and all first-generation, drug-resistant mutants of the protein is identified by determining in vitro the identity of each distinct, first-generation, drug-resistant mutant form of a protein that may arise in vivo in response to a first drug targeted thereagainst, wherein the distinct, first-generation, drug-resistant mutants contain a limited number of resistance-conferring mutations, and then determining in vitro the identity of one or more auxiliary drugs that inhibit all of the first-generation, drug-resistant mutants of the protein, wherein the first drug and the one or more auxiliary drugs represent the combination of drugs.

Abstract: Methods and gene regulator fusion proteins are disclosed utilizing a bacterial reporter system to quickly and easily identify mutations of a target protein, such as a protease, that confer resistance to a chemotherapeutic agent directed against that target protein.

Abstract: The present invention provides methods and pharmaceutical preparations that inhibit the growth of bacterial microorganisms. Additionally, the present invention provides methods and pharmaceutical preparations that kill bacterial microorganisms.

Abstract: The present invention provides methods and pharmaceutical preparations that inhibit the growth of bacterial microorganisms. Additionally, the present invention provides methods and pharmaceutical preparations that kill bacterial microorganisms.

Abstract: The present invention provides methods and pharmaceutical preparations that inhibit the growth of bacteria microorganisms. Additionally, the present invention provides methods and pharmaceutical preparations that kill bacterial microorganisms.

Abstract: An in vitro method for predicting the identity of distinct, first-generation, drug-resistant, biologically-active, HIV protease mutants that may emerge in vivo in response to a drug targeted thereagainst. In a preferred embodiment, the in vitro method comprises the steps of (a) preparing, in the presence of the drug, a comprehensive library of all first-generation mutants of the protease differing therefrom by at least one and preferably no more than three amino acid substitutions, each of the protease mutants being generated as part of a polyprotein with the HIV reverse transcriptase protein; (b) isolating, in vitro, first-generation, drug-resistant, biologically-active, mutant proteases from said library by assaying for biological activity of the reverse transcriptase protein; and (c) identifying the distinct, first-generation, biologically-active, mutant proteases so isolated.

Abstract: Processes for preparing a single enantiomer of an .alpha.,.alpha.-disubstituted-.alpha.-hydroxy acetic acid, especially cyclohexylphenylglycolic acid (CHPGA), is disclosed. The processes employ cyclic 1,2-aminoalcohols as chiral auxiliaries by forming diastereomeric esters of aminoalcohols or diastereomeric amides of oxazolidines. ##STR1## Intermediates useful in the process are also disclosed.

Abstract: Processes for preparing a single enantiomer of an .alpha.,.alpha.-disubstituted-.alpha.-hydroxy acetic acid, especially cyclohexylphenylglycolic acid (CHPGA), is disclosed. The processes employ cyclic 1,2-aminoalcohols as chiral auxiliaries by forming diastereomeric esters of aminoalcohols or diastereomeric amides of oxazolidines. ##STR1## Intermediates useful in the process are also disclosed.

Abstract: A method for identifying, in vitro, distinct, drug-resistant, biologically-active mutants of a protein that may emerge in vivo in response to a drug targeted against the protein is disclosed. The method involves preparing, by heterologous expression of a library of nucleotide sequences, a complete library of mutant proteins accessible in a single generation. The mutant proteins from the library that are drug resistant are identified. When all the first generation mutants have been identified in the above manner, a combination of drugs can be identified that will block the development of resistance. The same technique allows evaluation of the ultimate clinical efficacy of a drug targeted against the protein by comparing the number of resistant first generation mutants. A preferred protein is an HIV protease.

Abstract: Method for inactivating non-enveloped viruses using a viricide-potentiating agent. In a preferred embodiment, the method may be used to inactivate non-enveloped viruses present within a sample of whole blood or a blood product and comprises (a) adding to the blood sample a photoactivatable viricide, such as a psoralen, hypericin, methylene blue, toluidine blue or the like, which, when activated, is effective in inactivating enveloped viruses; (b) adding to the blood sample a viricide-potentiating chemical agent that increases the sensitivity of non-enveloped viruses to the activated viricide; and (c) activating the photoactivatable viricide.

Abstract: Described herein is a process for resolving a racemic (C>3) alkyl (R, S) chroman-2-carboxylate compound useful as intermediates in the synthesis of optically pure pharmaceutical compounds is disclosed. The process utilizes a microbial enzyme derived from Serratia marcescens to catalyze the enantioselective hydrolysis of the (C>3) alkyl (S)-chroman-2-carboxylate enantiomer of the racemic mixture to its corresponding carboxylic acid at a faster rate than the R-enantiomer. An enantiomerically pure S-configured carboxylic acid is thereby formed which can undergo acidic esterification to provide an optically pure (C>3) alkyl (S)-chroman-2-carboxylate intermediate for subsequent pharmaceutical synthesis. The nonhydrolyzed (C>3) alkyl (R)-chroman-2-carboxylate enantiomer can also be isolated to provide an optically pure pharmaceutical precursor.

Abstract: A process for resolving racemic alkyl 1,4-benzodioxan-2-carboxylates useful as intermediates in the synthesis of optically pure pharmaceutical compounds such as (S)-doxazosin is disclosed. The process utilizes a microbial enzyme derived from Serratia marcescens to catalyze the enantioselective hydrolysis of the alkyl (S)-1,4-benzodioxan-2-carboxylate enantiomer of the racemic mixture to its corresponding carboxylic acid at a faster rate than the R-enantiomer. An enantiomerically pure S-configured carboxylic acid is thereby formed for subsequent pharmaceutical synthesis. The nonhydrolyzed alkyl (R)-1,4-benzodioxan-2-carboxylate enantiomer can also be isolated and racemized, and the enzymatic hydrolysis reaction repeated.

Abstract: A process for producing substantially pure R-ketoprofen by the enantioselective hydrolysis of racemic ketoprofen choline ester is disclosed. The process utilizes either intact Beauveria bassiana hyphae or an R-specific ester hydrolase isolated therefrom. The ester hydrolase has an approximate molecular weight of 17,800 daltons and an N-terminal sequence of Ala-Pro-Asp-W-Ile-Ile-Gln-Gly-Leu-Ser-Arg-Ala-X-Asp-Gly-Gln-Asp.

Abstract: A culture for the production of xanthophylls comprising Nospongiococcum excentricum ATCC 40335 and mutants thereof. The culture having a dry cell weight xanthophyll content of at least about 0.65% and being capable of growing to a cell density of greater than about 40 grams per liter. The culture also comprising: carbon, phosphate, sulfate, iron, magnesium, and nitrogen.

Abstract: Mutations are induced in a microorganism selected from the species Saccharomyces cerevisiae or from the species Candida flareri. The resulting mutants are cultured in the presence of a fermentation inhibitor, such as acetaldehyde, ephedrine or PAC-dione, to form colonies having resistance to the inhibitor. Cells from the colonies are isolated and tested for yield of phenyl acetyl carbinol (PAC) in a fermentation with benzaldehyde and pyruvate. Yeast cells from the colonies that produce elevated levels of PAC are selected for use in subsequent fermentations. PAC is useful as an intermediate in the preparation of l-ephedrine and d-pseudoephedrine, two well-known medicinal chemicals.

Abstract: A process for enantioselectively converting an aldehyde, a bisulfite adduct of an aldehyde or a glycidate to a chiral carboxylic acid is disclosed. The process utilizes a microorganism or an enzyme preparation from a microorganism and is particularly useful for producing NSAIDs of the profen class from readily available precursors. Preferred microorganisms are Gram-negative rod bacteria.

Abstract: A biocatalytic method of preparing optically pure precursors of paroxetine and a method of preparing paroxetine therefrom are disclosed. A racemic trans ester precursor compound of paroxetine is first prepared. The racemic trans ester precursor compound comprises a mixture of (3S,4R) and (3R,4S) enantiomers. The (3R,4S) enantiomer is hydrolyzed biocatalytically to the corresponding (3R,4S)-trans carboxylic acid or alternatively, the (3S,4R) enantiomer is biocatalytically hydrolyzed the to (3S,4R)-trans carboxylic acid in a reaction catalyzed by a isolated enzyme or a microorganism. In the first instance, the unhydrolyzed (3S,4R) enantiomer is separated from the (3R,4S)-trans carboxylic acid, whereas in the second instance the (3S,4R)-trans carboxylic acid is separated from the unhydrolyzed (3R,4S) enantiomer. The (3S,4R) enantiomer obtained following the selective hydrolysis is reduced to form a (-)-trans-(3S,4R) primary alcohol precursor of paroxetine.

Abstract: A method of systematically generating and isolating highly flavinogenic strains of Candida famata. The strains Candida famata GA18Y8-6#2 dgr and Candida famata GA18Y8-6#2#11 have been developed and produce yields of ca. 7.0 to 7.5 grams per liter per 6 days. The method includes a combination of iterative mutagenizing steps and protoplast fusion steps performed on the parent strain and the descendant strains which are selected following each step according to a screening protocol.

Abstract: Strains of yeast of the species Candida famata are disclosed which can produce 10 grams of riboflavin per liter in 6 days, and in particular, strains identified by ATCC Accession Nos. 20849 and 20850. Riboflavin yields of more than 20 grams per liter in 200 hours have been achieved. Strains of the present invention have increased sensitivity to iron inhibition of flavinogenesis and have enhanced riboflavin production per cell at increased iron concentrations in the fermentation medium. The invention also is directed toward a process for selecting improved microorganisms which are resistant to inhibition of growth by depleted medium. Such selected mircoorganisms are then tested for riboflavin overproduction. The present invention is also directed toward a selection process in which mutated microorganisms are cultured in the presence of tubercidin, a purine analog. Mutant strains resistant to tubercidin are then tested for riboflavin over-production.