History and Prospects of Drug Discovery and Development Collaboration between Industry and Academia.

Research collaborations and licensing deals are critical for the discovery and development of life-saving drugs. This practice has been ongoing since the inception of the pharmaceutical industry. The current process of drug discovery and development is complex, regulated, and highly regimented, having evolved over time.

Nutritional control of antibiotic production by Streptomyces platensis MA7327: importance of l-aspartic acid.

Streptomyces platensis MA7327 is a bacterium producing interesting antibiotics, which act by the novel mechanism of inhibiting fatty acid biosynthesis. The antibiotics produced by this actinomycete are platensimycin and platencin plus some minor related antibiotics. Platensimycin and platencin have activity against antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus; they also lack toxicity in animal models.

Development of a chemically defined medium for the production of the antibiotic platensimycin by Streptomyces platensis.

The actinomycete Streptomyces platensis produces two compounds that display antibacterial activity: platensimycin and platencin. These compounds were discovered by the Merck Research Laboratories, and a complex insoluble production medium was reported. We have used this medium as our starting point in our studies.

Development of a semi-defined medium supporting production of platensimycin and platencin by Streptomyces platensis.

Platensimycin and platencin are compounds that were discovered at Merck Research Laboratories and have shown promising antibacterial activity. They are both produced in fermentation by the actinomycete Streptomyces platensis. Merck reported a crude, insoluble production medium to produce the antibiotics.

New potential antitumor compounds from the plant Aristolochia manshuriensis as inhibitors of the CDK2 enzyme.

The 70% aqueous methanolic extract of the Chinese plant Aristolochia manshuriensis was found to contain two novel substituted phenanthrene compounds, SCH 546909 (1), and another phenanthrene glycoside (2). The structures of 1 and 2 were established based on NMR studies. They were identified as inhibitors of the CDK2 enzyme.

Semi-synthetic aristolactams--inhibitors of CDK2 enzyme.

Several analogs of aristolochic acids were isolated and derivatized into their lactam derivatives to study their inhibition in CDK2 assay. The study helped to derive some conclusions about the structure-activity relation around the phenanthrin moiety. Semi-synthetic aristolactam 21 showed good activity with inhibition IC50 of 35 nM in CDK2 assay.

Caryophyllenes from a fungal culture of Chrysosporium pilosum.

Four new caryophyllene derivatives, Sch 725432 (1), Sch 601253 (2), Sch 601254 (3), and Sch 725434 (4), were isolated from the fungal fermentation broth of Chrysosporium pilosum by reversed-phase HPLC purification. The structure elucidation of trioxygenated caryophyllenes 1-4 was accomplished on the basis of spectroscopic data interpretation. Sch 725434 (4) possesses a dihydrofuran-3-one ring, forming a tricyclic ring skeleton, which represents an unprecedented ring skeleton for the caryophyllene-type of sesquiterpenes.

Isolation, structural determination, synthesis and quantitative determination of impurities in Intron-A, leached from a silicone tubing.

Investigation of unexpected levels of impurities in Intron product has revealed the presence of low levels of impurities leached from the silicone tubing (Rehau RAU-SIK) on the Bosch filling line. In order to investigate the effect of these compounds (1a, 1b and 2) on humans, they were isolated identified and synthesized. They were extracted from the tubing by stirring in Intron placebo at room temperature for 72 h and were enriched on a reverse phase CHP-20P column, eluting with gradient aqueous ACN and were separated by HPLC.

Sch 213766, a novel chemokine receptor CCR-5 inhibitor from Chaetomium globosum.

A novel fungal secondary metabolite, Sch 213766 was isolated from the fungal fermentation broth of Chaetomium globosum as the chemokine receptor CCR-5 inhibitor and shown to be the methyl ester of the previously described tetramic acid Sch 210972 on the basis of UV, MS and NMR spectral data analyses. Sch213766 exhibited an IC(50) value of 8.6 muM in the CCR-5 receptor in vitro binding assay.

Novel steroidal saponins, Sch 725737 and Sch 725739, from a marine starfish, Novodinia antillensis.

Bioassay-guided fractionation of an active fraction from an extract of a marine starfish, Novodinia antillensis, led to the isolation and identification of two new saponins, Sch 725737 (1) and Sch 725739 (2). Compound 1 was identified as the NaV1.8 inhibitor with IC(50) of approximately 9 microM.

A new hydrogenated azaphilone Sch 725680 from Aspergillus sp.

A new hydrogenated azaphilone Sch725680 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was achieved based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 8 and 64 microg/ml, respectively.

Chemokine receptor CCR-5 inhibitors produced by Chaetomium globosum.

Two novel chemokine receptor CCR-5 inhibitors, Sch 210971 (1) and Sch 210972 (2), were isolated from the fungal fermentation broth of Chaetomium globosum by normal- and reversed-phase HPLC purifications. The structure determination of 1 and 2 was accomplished on the basis of UV, MS, and NMR spectral data analyses including COSY, NOESY, HMQC, and HMBC experiments. The structure and relative configuration of 2 were determined unequivocally by X-ray crystallographic analysis.

A new 5-alkenylresorcinol sch 725681 from Aspergillus sp.

A new 5-alkenylresorcinol Sch725681 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was accomplished based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 16 and 64 microg/ml, respectively.

Drug discovery from natural products.

Natural product compounds are the source of numerous therapeutic agents. Recent progress to discover drugs from natural product sources has resulted in compounds that are being developed to treat cancer, resistant bacteria and viruses and immunosuppressive disorders. Many of these compounds were discovered by applying recent advances in understanding the genetics of secondary metabolism in actinomycetes, exploring the marine environment and applying new screening technologies.

Exploiting new approaches for natural product drug discovery in the biotechnology industry.

In recent years, large pharmaceutical companies have significantly reduced or eliminated the search for new therapeutic agents from natural sources. In spite of the many successes from natural product drug discovery, these companies have chosen to focus on compound libraries as the source of new lead compounds. Smaller biotechnology companies are continuing the search for novel natural products by developing and employing new and innovative approaches.

A new antitumor compound from the plant Oryctanthus sp. as a VEGF receptor binding inhibitor.

The 70% aqueous methanolic extract of the Peruvian plant Oryctanthus sp. was found to contain a novel saccharide of a diene alpha,omega-diacid. Compound 1 was identified as an inhibitor of the VEGF receptor.

New antibiotic Sch 725424 and its dehydration product Sch 725428 from Kitasatospora sp.

A new microbial metabolite Sch 725424 (1) was isolated from the culture of Kitasatospora sp. The structure elucidation of 1 was accomplished based on NMR spectroscopic analyses as well as extensive structure elucidation of its dehydration product Sch 725428 (2). Compound 1 showed inhibitory activity against Staphylococcus aureus with MIC values 1-2 microg/ml, and also displayed weak antifungal activity against Saccharomyces cerevisiae (PM503) with an MIC 32 microg/ml.

Three new compounds from the plant Lippia alva as inhibitors of chemokine receptor 5 (CCR5).

The 70% aqueous methanol extract of the Peruvian plant Lippia alva (Verbenaceae) was found to contain three novel compounds, 1, 2, and 3, which were identified as inhibitors of the chemokine receptor CCR5. The structures of 1-3 were established based on extensive NMR studies. Compounds 1-3 inhibited CCR5 receptor signaling as measured by a calcium mobilization assay with IC(50) values of 5.

Two novel antibiotics, Sch 419558 and Sch 419559, produced by Pseudomonas fluorescens: effect on activity by overexpression of RpoE.

Two new secondary metabolites designated as Sch 419558 (1) and Sch 419559 (2), were isolated from the fermentation broth of Pseudomonas fluorescens. Structure elucidation of 1 and 2 was accomplished by spectroscopic data analyses including MS and NMR experiments. Both compounds were identified as lipopeptides containing valine and threonine linked with 1-amino-1-hydroxy-heptadec-9-en-2-one or 1-amino-1-hydroxy-pentadecan-2-one carbon chains, respectively.

Two new bacterial DNA primase inhibitors from the plant Polygonum cuspidatum.

The 70% aqueous methanolic extract of the Peruvian plant Polygonum cuspidatum sp. was found to contain two novel phenolic saccharides 1 and 2, which were identified as inhibitors of the bacterial DNA primase enzyme. Structures of these two compounds were established based on high resolution NMR studies.

Isolation and structure elucidation of Sch 642305, a novel bacterial DNA primase inhibitor produced by Penicillium verrucosum.

A novel primase inhibitor, Sch 642305 (1), was isolated from the fermentation broth of the fungal culture Penicillium verrucosum. The structure of 1 was elucidated on the basis of MS and NMR spectroscopic data as a new and unusual bicyclic 10-membered macrolide. The absolute configuration of the asymmetric centers was determined by X-ray crystallographic analysis of the p-bromobenzoate derivative (3).