Current Medicinal Chemistry (v.18, #22)

The “3rd International Conference on Drug Discovery and Therapy” was held from February 7-10, 2011 at DubaiWomen’s College, UAE. It was a major scientific event with several hundred lectures delivered in 35 thematic sessions, posterpresentations and an associated commercial exhibition. The 3rd International Conference on Drug Discovery and Therapyprovided renowned scientists the opportunity to present their cutting edge researches in the field of drug development andtherapy. The participants included the leading luminaries in the field. The Nobel Laureates who honored the event with theirprestigious presence were: Prof. Dr. Warner Arber (USA), Prof. Dr. Robert Huber (Germany), Prof. Dr. Jean-Marie Lehn(France), Prof. Dr. Ferid Murad (USA), and Prof. Dr. Erwin Neher (Germany). The honorable Fellows of Royal Society(FRS) attended this event were: Prof. Sir Alen Roy Fersht, (U.K.) Prof. Dr. Goverdhan Mehta, (India), Prof. Dr. Atta urRahman (Pakistan). This conference provided a platform to more than 700 pharmaceutical scientists, doctors and clinical researchers toelucidate upon the latest discoveries and researches in their respective fields. The conference agenda span over 300 lecturesaccompanied by 250 poster presentations catering to 35 major drug discovery disciplines. The third conference offered an opportunity for exchange of ideas amongst leading pharmaceutical scientists, clinicians andinternists. Top international scientists and clinicians presented their cutting-edge discoveries on new therapeutic drugs,highlighted the burgeoning field of Translational Medicine, and the major advances from "bench to bedside" research andpractice The presentations by leading exponents in their respective fields spanned the interdisciplinary areas of pre-clinical andclinical drug discovery and drug therapy. An entire session was dedicated to Academic CRO/Industrial Collaborations in DrugDiscovery. All the sessions were well attended by the participants and were greatly appreciated. All in all it was a wonderful event that the participants thoroughly enjoyed. A selection of some of the papers are beingpresented in this special issue of Current Medicinal Chemistry.

Recent progress in understanding of the nitric oxide and cGMP signaling pathway provided evidence for mechanism of actionof known drugs and identified novel targets for drug development. These discoveries resulted in numerous efforts in drug and formulationdiscovery. Some of the most promising approaches were applied for efficient therapies of various diseases.

Alzheimer’s disease (AD) is the most common form of dementia in the older people and 7th leading cause of death in theUnited States. Deposition of amyloid-beta (Aβ) plaques, hyperphosphorylation of microtubule associated protein tau (MAPT), neuroinflammationand cholinergic neuron loss are the major hallmarks of AD. Deposition of Aβ peptides, which takes place years before theclinical onset of the disease can trigger hyperphophorylation of tau proteins and neuroinflammation, and the latter is thought to be primarilyinvolved in neuronal and synaptic damage seen in AD. To date, four cholinesterase inhibitors or ChEI (tacrine, rivastigmine,donepezil and galantamine) and a partial NMDA receptor antagonist (memantine) are the only approved treatment options for AD. However,these drugs fail to completely cure the disease, which warrants a search for newer class of targets that would eventually lead to effectivedrugs for the treatment of AD. In addition to selected pharmacological agents, botanical and medicinal plant extracts are also beinginvestigated. Apart from its culinary use, garlic (Allium sativum) is being used to treat several ailments like cancer and diabetes.Herein we have discussed the effects of a specific ‘Aged Garlic Extract’ (AGE) and one of its active ingredients, S-allyl-L-cysteine(SAC) in restricting several pathological cascades related to the synaptic degeneration and neuroinflammatory pathways associated withAD. Thus, based on the reported positive preliminary results reviewed herein, further research is required to develop the full potential ofAGE and/or SAC into an effective preventative strategy for AD.

Alzheimer’s disease (AD) is the most common form of dementia in the United States and is increasing in prevalence everyyear throughout the world. Recent clinical trial failures highlight the need for further insights into the molecular events that underlie theneurobiology of AD. Pathological aberrations in AD are believed to result, in part, from excess accumulation of amyloid-beta peptide(Aβ), a product of Aβ precursor protein (APP). Targeting APP levels would then be expected to reduce Aβ production in all forms ofAD. Therefore, clarifying the regulatory network that governs APP expression is likely to reveal molecular players that could serve asnovel drug targets. This review highlights recent work demonstrating the involvement of microRNA (miRNA) in this regulatory network.MiRNA are small, non-coding RNA that interact with target mRNA at sites of imperfect complementarity and mediate translational inhibitionor transcript destabilization. We first review the neurobiology of AD and describe current therapeutic strategies. We then reviewtranscriptional and post-transcriptional mechanisms utilized by cells to control APP expression. We conclude by highlighting recentwork, including our own, which suggests miRNA are integral components of this regulatory framework and potential targets for futureAD therapeutics.

Pharmacotherapy of Borderline Personality Disorder: A Systematic Review by S. Bellino, C. Rinaldi, P. Bozzatello, F. Bogetto (3322-3329).
Borderline Personality Disorder (BPD) is a common disorder in psychiatric practice and drugs are widely used in its treatment,targeting symptom clusters, such as affective dysregulation, impulsive-behavioural dyscontrol, and cognitive-perceptual symptoms. Inlast period, a growing number of studies on pharmacological treatment of BPD have been performed, but different proposals of treatmentguidelines are not completely in accordance on drug indications for BPD patients. This article reviews double-blind randomized controlledtrials comparing active drugs versus placebo and drugs versus drugs, published between 1990 and 2010 and focused on the treatmentof borderline personality disorder. Different classes of psychoactive agents, such as antipsychotics, mood stabilizers, antidepressants,and dietary supplementation were tested in BPD patients. More recent evidences suggest that mood stabilizers (topiramate, valproateand lamotrigine), second generation antipsychotics (olanzapine and aripiprazole) and omega-3 fatty acids can be useful to treat affectivesymptoms and impulsive-behavioural dyscontrol in BPD patients. Moreover, antipsychotics significantly improve cognitivesymptoms in patients with BPD. SSRIs were found effective in decreasing severity of depressed mood, anxiety and anger, mainly in subjectswith a concomitant affective disorder. Effects of antidepressants on impulsive behaviours are uncertain. Further studies are neededto improve methods of trials and confirm these findings.

Brain capillary endothelial cells form the blood-brain barrier (BBB) that denotes a major restraint for drug entry to the brain.The identification of many new targets to treat diseases in the brain demands novel thinking in drug design as new therapeutics could oftenbe proteins and molecules of genetic origins like siRNA, miRNA and cDNA. Such molecules are otherwise prevented from entry intothe brain unless encapsulated in drug carriers. The desirable entry of such large, hydrophilic molecules should be made by formulation ofparticular drug carriers that will enable their transport into the brain endothelium, or even through the endothelium and into the brain.This manuscript reviews the potential of different drug-carriers for therapy to the brain with respect to their targetability, biocompatibility,toxicity and biodegradability.

The HIV-1 integrase (IN) and reverse transcriptase (RT) are essential enzymes in the virus cycle. RT is crucial for the retrotranscriptionof the RNA viral genome, while IN is involved in the insertion in host chromosome of the proviral double strand DNA producedby RT. This enzyme has two associated functions: the RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) and theribonuclease H (RNase H). The RNase H function catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplexreplication intermediate. Since the discovery that catalytic cores of both HIV-1 RNase H and IN are folded in a very similar way, havevery similar active site geometries, and show the same DDE triad absolutely required for catalytic activity, some researches were devotedto study IN and RNase H dual inhibitor. Our decennial interest in design and synthesis of IN inhibitors led us to study the activity of ourcompounds also on RNase H activity. The results of the activities showed by pyrrolyl and quinolonyl diketo acids are reported and discussed.

Novel Modular DNA Aptamer for Human Thrombin with High Anticoagulant Activity by E. Zavyalova, A. Golovin, R. Reshetnikov, N. Mudrik, D. Panteleyev, G. Pavlova, A. Kopylov (3343-3350).
Aptamers based on nucleic acids are a promising alternative to antibodies in therapy and diagnostics. Several DNA aptamersagainst human thrombin have been developed by selection from random libraries: a 15-mer and its derivatives, a 29-mer, and a 31-mer.Some of them are patented and already under clinical trial. The 15-mer structure was determined by X-ray and NMR and turned out to bea monomolecular antiparallel G-quadruplex. The other aptamers mentioned above have higher inhibitory activity than the initial 15-mer,but there are not yet structural data explaining this phenomenon. Here, the initial 15-mer, 31-mer, and novel RA-36 aptamers are comparedto establish the structure-function correlation, providing a solid ground for further rational aptameric drug design. For the moleculardynamic simulation of aptamers, the force field parmbsc0 was ported onto GROMACS, and the main stabilizing parameters were revealed,leading to the novel DNA aptamer RA-36. The functional properties of the DNA aptamers were studied by conventional coagulationtests, which do not directly elucidate the mechanism of thrombin inhibition by aptamers. Improved turbidimetric measurements provideddata to develop detailed kinetics showing that the 31-mer and RA-36, in contrast to the 15-mer, are competitive inhibitors. Thesedata revealed RA-36 to be an efficient thrombin inhibitor with a dose-dependent effect. Animal tests of the studied DNA aptamers suggestedan unexpected species-specificity of the novel RA-36.

Anti-Inflammatory and Antioxidant Properties of a New Arylidene-Thiazolidinedione in Macrophages by L.A. Faine, M. Rudnicki, F.A. Cesar, B.L. Heras, L. Bosca, E.S. Souza, M.Z. Hernandes, S.L. Galdino, M.C.A. Lima, I.R. Pitta, D.S.P. Abdalla (3351-3360).
Thiazolidinediones (TZDs) are a class of drugs used for treatment of type 2 diabetes. However, the therapy with currentlyavailable TDZs (e.g. rosiglitazone) is associated with important side effects, such as edema and weight gain, suggesting that the investigationof alternative TZDs with better pharmacological properties is warranted. In this study, we investigated both anti-inflammatory andantioxidant properties of a new chemically modified TZD, the arylidene-thiazolidinedione 5-(4-methanesulfonyl-benzylidene)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione (SF23), and compared the results to those obtained with rosiglitazone. We found that our SF23 displays aweaker affinity for PPAR, up-regulating in a lower magnitude the expression of both PPAR and CD36 compared to rosiglitazone. Inlipopolysaccharide (LPS)-stimulated macrophages, SF23 decreased nitrite production and attenuated the mRNA expression of both iNOSand COX-2. These anti-inflammatory effects were comparable to those obtained with rosiglitazone. Interestingly, SF23, but not rosiglitazone,prevented LPS-induced mitochondrial membrane hyperpolarization, apoptosis, reactive oxygen species (ROS) generation, and theexpression of NADPH oxidase subunits, Nox1 and Nox2. In addition, in macrophages from Nrf2-/- mice, SF23 protected against LPSinducedcellular death and ROS production, whereas rosiglitazone was only able to protect normal Nrf2+/+ cells against oxidative injury,suggesting that, unlike rosiglitazone, the antioxidant activity of SF23 might be Nrf2-independent. Finally, in macrophages exposed tohigh concentrations of glucose, SF23 induced significant increases in the mRNA expression of glucose transporters, insulin receptor substrateand mitoNEET. Altogether, our data indicate that our new chemically modified TDZ displays similar anti-inflammatory properties,but superior antioxidant effects on the LPS-stimulated macrophages compared to rosiglitazone.

Towards Improved Therapeutic CORMs: Understanding the Reactivity of CORM-3 with Proteins by T. Santos-Silva, A. Mukhopadhyay, J.D. Seixas, G.J.L. Bernardes, C.C. Romao, M.J. Romao (3361-3366).
The biological role of carbon monoxide (CO) has completely changed in the last decade. Beyond its widely feared toxicity,CO has revealed a very important biological activity as a signaling molecule with marked protective actions namely against inflammation,apoptosis and endothelial oxidative damage. Its direct use as a therapeutic gas showed significant and consistent positive results butalso intrinsic severe limitations. The possibility of replacing the gas by pro-drugs acting as CO-Releasing Molecules (CO-RMs) hasclearly been demonstrated with several experimental compounds. Transition metal carbonyls complexes have proven to be the most versatileexperimental CO-RMs so far. Presently, the challenge is to equip them with drug-like properties to turn them into useful pharmaceuticals.This requires studying their interactions with biological molecules namely those that control their pharmacokinetic and ADMEprofiles like the plasma proteins. In this account we analyze these questions and review the existing interactions between Metal Carbonylsand proteins. The recently explored case of CORM-3 is revisited to exemplify the methodologies involved and the importance of theresults for the understanding of the mode of action of such pro-drugs.

Nature Inspired Structured Surfaces for Biomedical Applications by H.K. Webb, J. Hasan, V.K. Truong, R.J. Crawford, E.P. Ivanova (3367-3375).
Nature has created an array of superhydrophobic surfaces that possess water-repellent, self-cleaning and anti-icing properties.These surfaces have a number of potential applications in the biomedical industry, as they have the potential to control protein adsorptionand cell adhesion. Natural superhydrophobic surfaces are typically composed of materials with a low intrinsic surface free-energy (e.g thecuticular waxes of lotus leaves and insect wings) with a hierarchical structural configuration. This hierarchical surface topography acts todecrease the contact area of water droplets in contact with the surface, thereby increasing the extent of the air/water interface, resulting inwater contact angles greater than 150°. In order to employ these surfaces in biotechnological applications, fabrication techniques must bedeveloped so that these multi-scale surface roughness characteristics can be reproduced. Additionally, these fabrication techniques mustalso be able to be applied to the material required for the intended application. An overview of some of the superhydrophobic surfacesthat exist in nature is presented, together with an explanation of the theories of their wettability. Also included is a description of some ofthe biomedical applications of superhydrophobic surfaces and fabrication techniques that can be used to mimic superhydrophobic surfacesfound in nature.

Nanotechnology and tissue engineering are promising scientific fields in the development of advanced materials useful to humanhealth. This article describes the preparation of a nanocarrier for the controlled release of a photosensitizer compound associatedwith low-level light therapy for skin wound healing treatment and applicable to other skin diseases. A biological model was used as an invitro skin equivalent based on a three-dimensional culture of fibroblasts and mesenchymal stem cells and denominated by dermal equivalent(DE). Results show that it is possible to use the photomodulation process to control the wound healing in a scratching process and toinduce the biomolecules release, both of which are related with the inflammatory wound healing process. In the studies, the MMP-2 andMMP-9 expression from zymography analyses were evaluated. All results showed a dependence on enzymatic activity relating to lowlevellaser applications which indicates a potential application in wound healing processes based on phototherapy and nanotechnology.

Involvement of the ADAM 12 in Thrombin-Induced Rat's VSMCs Proliferation by K. Smiljanic, B. Dobutovic, M. Obradovic, D. Nikolic, P. Marche, E.R. Isenovic (3382-3386).
Cardiovascular disease is the largest single cause of mortality and its major underlying pathology is atherosclerosis. The proliferationof vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of the various vascular diseases, including atherosclerosisand hypertension. Thrombin (Thr) is involved in the abnormal proliferation of VSMCs associated with atherosclerosis and hypertension.ADAMs (A Disintegrin And Metalloproteinase) are transmembrane metalloproteinases, belonging to the adamalysins group, that are distinctfrom matrix metalloproteinases (MMPs) in a way as they have an extracellular disintegrin domain and cytoplasmic domain that canassociate with intracellular proteins. There is limited knowledge about the presence of ADAM metalloproteinase activity in Thr-inducedVSMCs proliferation. Therefore, this review examines recent findings in signaling mechanisms employed by Thr in modulating theregulation of proliferation of VSMCs with particular emphasis on involvement of ADAM 12 which has been identified as an importantmediator of VSMCs hypertrophy and vascular diseases. These findings are critical for understanding the role of Thr in vascular biologyand vascular diseases.

Targeting the Multidrug ABCG2 Transporter with Flavonoidic Inhibitors: In Vitro Optimization and In Vivo Validation by A. Boumendjel, S. Macalou, G. Valdameri, A. Pozza, C. Gauthier, O. Arnaud, E. Nicolle, S. Magnard, P. Falson, R. Terreux, P.-A. Carrupt, L. Payen, A. Di Pietro (3387-3401).
This review describes the breast cancer resistance protein ABCG2 through its structure, functional roles and involvement incell multidrug resistance, especially in cancer cells resistance to chemotherapeutics. The different types of known inhibitors are described,some being non-selective, since they also bind to other targets, and others being quite specific such as flavonoids. The differentclasses of active flavonoids and other polyphenols are described, some as plant natural compounds, but most of them being prepared andderivatized through medicinal chemistry. Quantitative structure-activity relationships of the ability of flavones, chalcones, xanthones,acridones and various benzopyrane/benzofurane derivatives to inhibit ABCG2-mediated drug efflux have led to pharmacophores and molecularmodels allowing to optimize the available hit compounds and to design new-generation lead compounds. Interestingly, inhibitoryflavonoids are quite specific for ABCG2 versus ABCB1 and ABCC1, and appear either non-competitive or partially competitive towardsmitoxantrone efflux. Most compounds do not inhibit ATPase activity, and are assumed not to be transported themselves by the transporter.Some acridones, firstly optimized in vitro as potent inhibitors, are indeed efficient in vivo, against human xenografts in SCIDmice, more efficiently than gefitinib taken as a control. Future developments should open the way to more efficient/targeted modulatorsincluding (i) the potential interest of bimodulation by combining two different inhibitors, (ii) computer-assisted ligand-based drug designfor getting more potent and more specific inhibitors, (iii) structure-based drug design from ABCG2 molecular models allowing in silicoscreening and docking of new inhibitors.

Assessing Methods for Characterising Local and Global Structural and Biomechanical Properties of the Trabecular Bone Network by I. Sidorenko, R. Monetti, J. Bauer, D. Mueller, E. Rummeny, F. Eckstein, M. Matsuura, E.-M. Lochmueller, P. Zysset, C. Raeth (3402-3409).
We apply noval techniques, the Scaling Index Method (SIM), which reveals local topology of the structure, and theMinkowski Functionals (MF), which provide four global topological characteristics, to assess strength of the trabecular network of thehuman bone. We compare capabilities of these methods with the standard analysis, biomechanical Finite Element Method (FEM) andmorphological parameters, in prediction of bone strength and fracture risk. Our study is based on a sample of 151 specimens taken fromthe trabecular part of human thoracic and lumbar vertebrae in vitro, visualised using μCT imaging (isotropic resolution 26μm) and testedby uniaxial compression. The sample of donors is heterogeneous, consisting of 58 male and 54 female cadavers with a mean age of 80 ±10 years. To estimate the predictive power of the methods, we correlate texture measures derived from μCT images with the maximumcompressive strength (MCS) as obtained in biomechanical tests. A linear regression analysis reveals that the failure load estimated byFEM shows the highest correlation with MCS (Pearson's correlation coefficient r=0.76). None of the methods in current study is superiorto the FEM: morphometric parameters give r<0.5, global topological characteristics show r=0.73 for the first Minkowski FunctionalMF1, which coincides with bone volume fraction BV/TV and r=0.61 for the second Minkowski functional MF2, which coincides withbone surface BS. Although scaling indices provided by SIM correlate only moderately with MCS (r=0.55), texture measures based on thenonlinear combination of local (SIM) and global (MF) topological characteristics demonstrate high correlation with experimental MCS(r=0.74) and with failure load estimated by FEM (r=0.95). Additional advantage of the proposed texture measures is possibility to revealthe role of the topologically different trabecular structure elements for the bone strength.

Progress Towards Discovery of Antifibrotic Drugs Targeting Synthesis of Type I Collagen by D. Fritz, L. Cai, L. Stefanovic, B. Stefanovic (3410-3416).
Type I collagen is the most abundant protein in human body. Fibrosis is characterized by excessive synthesis of type I collagenin parenchymal organs. It is a leading cause of morbidity and mortality worldwide, about 45% of all natural deaths are attributable tosome fibroproliferative disease. There is no cure for fibrosis. To find specific antifibrotic therapy targeting type I collagen, critical molecularinteractions regulating its synthesis must be elucidated. Type I and type III collagen mRNAs have a unique sequence element atthe 5' end, the 5' stem-loop. This stem-loop is not found in any other mRNA. We cloned LARP6 as the protein which binds collagen 5'stem-loop with high affinity and specificity. Mutation of the 5' stem-loop or knock down of LARP6 greatly diminishes collagen expression.Mice with mutation of the 5' stem-loop are resistant to development of liver fibrosis. LARP6 associates collagen mRNAs with filamentscomposed of nonmuscle myosin; disruption of these filaments abolishes synthesis of type I collagen. Thus, LARP6 dependent collagensynthesis is the specific mechanism of high collagen expression seen in fibrosis. We developed fluorescence polarization (FP)method to screen for drugs that can inhibit binding of LARP6 to 5' stem-loop RNA. FP is high when LARP6 is bound, but decreases tolow levels when the binding is competed out. Thus, by measuring decrease in FP it is possible to identify chemical compounds that candissociate LARP6 from the 5' stem-loop. The method is simple, fast and suitable for high throughput screening.

It has been well propounded that there exists five basic taste modalities, e.g., sweet, sour, bitter, salty and umami. Recent compellingevidence from rodents and human beings raises the possibility for an additional sixth taste modality devoted to the perception oflipids. A number of studies have suggested that lingual CD36, a glycoprotein, mainly expressed by circumvallate papillae of the tongue,might be implicated in the perception of dietary fat taste. G protein-coupled receptors (GPCRs) are important signaling molecules formany aspects of cellular function. It has been recently shown that these receptors particularly GPR40 and GPR120 might also be involvedin lipid taste perception. In this article, we highlight the cell activation mechanisms, responsible for the downstream cell signalingwhich might help understand the lipid-mediated regulation of feeding behavior, critically involved in the development of several diseaseslike obesity and other metabolic disorders. We also raise the question whether lipid gustatory cells can be the target of anti-obesity strategies.

Anticholinesterasic, Nematostatic and Anthelmintic Activities of Pyridinic and Pyrazinic Compounds by M. Valli, A. Danuello, M. Pivatto, J.C. Saldana, H. Heinzen, L. Dominguez, V.P. Campos, S.R. Marqui, M.C.M. Young, C. Viegas Jr., D.H.S. Silva, V.S. Bolzani (3423-3430).
In the search for acetylcholinesterase inhibitors as a potential target for the discovery of anthelmintic drugs, a series of 27pyridinic and pyrazinic compounds have been designed on the basis of molecular hybridization of two known AChE inhibitors, namely,tacrine and (-)-3-O-acetylspectaline, and on the concept of isosterism. The synthesized compounds generally presented moderate anticholinesterasicactivities when compared with the positive control physostigmine, but one compound (ethyl 2-[(6-chloropyrazin-2-yl)sulfanyl] acetate, 11) exhibited an in vitro ability to immobilize the root-knot nematode Meloidogyne incognita that was highly comparableto that of the positive control Temik. Moreover, in anthelmintic assays against the gastrointestinal parasitic nematode Nippostrongylusbrasiliensis (L4), some of the compounds, such as (6-chloropyrazin-2-yl)sulfanyl ethanol (32, EC50 = 33 nM), presented activities thatwere considerably stronger than that of the positive control albendazole (EC50 = 340 nM). In the light of the positive results obtained inthe anthelmintic evaluations, the acute oral toxicity of the representative compound diethyl 2,2'-[(3-nitropyridine-2,6-diyl) bissulfanediyl]diacetate (7) was determined in rats, and the drug was shown to be non-toxic at a dose of 2000 mg/kg. These results, allied with the relativelysimple structures of the active compounds and their facile synthesis, highlight their potential use as anthelmintic or nematicidicagents.

Research has been conducted on the chemical and biological properties of combinatorial succinylated derivatives of interferon-γ with various levels of acylation, which create quasi-life, self-organizing ensembles. As a result of the research, it has been establishedthat acylation by succinic anhydride of two lysines in the structure of interferon-γ (Gammaferon) leads to both an increase in its affinityto cell receptors and a decrease in the time of maximum effect from 48 hours to 15 minutes. Moreover, treatment of cells with these interferonensembles led to the shielding of 100% of the cells after a 15-minute incubation period, whereas native interferon shielded no morethan 80% of the cells after 48 hours. Other ensembles also protected cells from viral action, but this protective effect did not exceed twohours in duration. The ensemble of succinylated interferon-γ with two modified lysines may hold promise for the treatment of severe viralinfections with fast courses, such as influenza and the diseases caused by the Ebola, Marburg, SARS, and other viruses.

Nonprofit Pharma: Solutions to What Ails the Industry by W.H. Moos, K. Kodukula (3437-3440).
Nonprofit organizations (NPOs) play an increasingly important role providing solutions to the significant challenges faced todayby both large pharmaceutical and smaller biotechnology companies, not to mention academia. NPOs chartered for the public benefitare common in the USA and in selected other parts of the world. SRI International, originally founded as the Stanford Research Institutein 1946, is one of the largest and most successful independent NPOs. To provide a perspective on NPO business models, a number of SRIcase studies spanning a broad range of technical and business initiatives will be summarized, including basic and contract research, discoveryand development of new drugs and biologics, pharmaceutical and biotech research and development and contract services, technologypivots, company spin-ins and spin-outs, and the creation of new NPOs. How to bridge the National Institute of Health's Valleyof Death and how to navigate the Food and Drug Administration's Critical Path will be discussed. We conclude with lessons learnedabout collaborations and routes to commercialization, along with food for thought for bioscience companies and outsourcing participants.Throughout, we attempt to explain why the role of NPOs is important to both the scientific and business communities and to patients andcaregivers.