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BOSTON & LISBON, Portugal--(BUSINESS WIRE)--Proterris, Inc., a clinical-development stage company focused on therapeutic applications of low-dose carbon monoxide, and Alfama, Inc. today announced the completion of a merger of the two companies that effectively creates the world’s dominant player in the field of carbon monoxide (CO) therapies. Proterris, which has a leading position in gaseous applications of CO, has acquired Alfama’s CO releasing molecule (“CORM”) assets, arguably the most extensive in the field. In connection with the asset acquisition, Proterris has acquired all of Alfama’s subsidiaries, including Alfama Lda. located near Lisbon, Portugal, which will be renamed Proterris (Portugal) Lda. In conjunction with the merger, Proterris will also implement a collaboration with Prof. Carlos Romão of the Institute of Chemical and Biological Technology (ITQB) of the New University of Lisbon (NOVA), one of the scientific pioneers and inventors of Aflama’s CORM assets, in order to further optimize CORM candidates for a variety of indications. Proterris looks to continue advancing its own gaseous Phase 2/3 trial in delayed graft function (DGF)prior to moving one of the CORM candidates into clinical trials, which the company aims to start in the next 18-24 months. “Alfama has discovered and developed unique families of CORMs which have demonstrated very potent anti-fibrotic, anti-inflammatory and cytoprotective effects with very low toxicity potential,” said Jeffrey D. Wager, M.D., Chairman & CEO of Proterris. “Until now, achievement of such drug-like profiles for CORMs has eluded scientists and companies alike. Alfama’s CORM assets represent excellent candidates for drug development for those indications which are less amenable to therapy with CO gas. In addition, by establishing Proterris (Portugal) Lda., we are now well-positioned to pursue a variety of European partnering and fundraising activities in both the private and public sectors. This coincides very well with the Series A fundraising campaign which are launching with the closing of this merger.” Dr. Wager has designed and structured multiple cross-border life science transactions in the past, including a major Japanese spin-out involving both Asian and American investors, a European Union-based corporate venture capital fund investing in both Europe and the U.S., and a specialty pharma roll-up in Brazil involving private equity funds from both Latin America and the U.S. “The merger of Alfama with Proterris represents a very synergistic and strategic fit between two companies with common goals, and substantially enhances corporate value for both sets of shareholders,” commented Nuno Arantes-Oliveira, founding Chief Executive of Alfama. “We are very glad to make Alfama part of Proterris’ exceptional IP portfolio, an important step in our evolution towards bringing low-dose CO therapies to patients.” Celso Guedes de Carvalho, CEO of Portugal Ventures, one of Alfama’s largest shareholders, added, “This transaction demonstrates how supporting investments for the ‘long-haul’ – given the capital and time required in the biotech sector – allows breakthrough technologies to reach patients. With regard to Alfama, their story demonstrates that when the technology is truly ground-breaking and the team strong and resilient, it is worth the wait. We believe this merger, with support from Portugal Ventures, will significantly increase the international visibility of the growing Portuguese Life Science startup ecosystem.” The Proterris-Alfama proposition for CO therapy is validated by almost $23 million in funding for three Phase 2 clinical trials using low dose CO gas. The U.S. National Institutes of Health (NIH) has funded these trials over the past five years for indications covered by patents licensed from a group of top U.S. universities or written by Proterris. About Alfama Alfama is the leading company in the development of Carbon Monoxide-Releasing Molecules (CORMs) for therapy. The company has produced hundreds of CORMs and obtained exceptional results in various animal models of chronic and acute human diseases. CORMs have the potential to expand CO-based therapy to a wide range of high-value indications, can be administered orally or intravenously, and offer a very attractive therapeutic window and safety profile. After acquiring hemoCORM Ltd of London, UK, Alfama came to control a diverse set of families of patents and patent applications on CORMs which together position the company as the undisputed leader in CORM technology. Alfama was founded in Portugal and received funding from venture capital agencies such as Portugal Ventures, along with private investors from the U.S., the U.K, Spain and Portugal. The Company assembled an international team of scientific and business leaders. Its founders included Roche scientist Werner Haas, New University of Lisbon Chemistry Professor Carlos Romão, Stan Kugell, its founding Chairman, and Nuno Arantes-Oliveira, its founding CEO. About Proterris Proterris, Inc. is a clinical-development stage company focused on therapeutic applications of low-dose carbon monoxide (CO). Leveraging CO’s demonstrated anti-fibrotic, anti-inflammatory and cytoprotective properties, Proterris is initially focused on developing CO for delayed graft function (DGF) in renal transplant recipients and idiopathic pulmonary fibrosis (IPF). Other indications, including pulmonary arterial hypertension (PAH) and acute respiratory distress syndrome (ARDS), are also being developed by the National Institutes of Health (NIH). CO has broad potential to significantly impact the lives of millions of patients suffering from a wide variety of both acute and chronic diseases. Proterris was founded on the pioneering science of Proterris co-founder Augustine M.K. Choi, M.D., who is Professor of Medicine and the Stephen and Suzanne Weiss Dean at Weill Cornell Medicine and Provost for Medical Affairs at Cornell University; and David J. Pinsky, M.D., the J. Griswold Ruth M.D. & Margery Hopkins Ruth Professor of Internal Medicine, Professor of Molecular and Integrative Physiology, Chief, Cardiovascular Medicine, and Director, Cardiovascular Center of the University of Michigan. Between them, Dr.’s Choi and Pinsky have generated an extensive body of mechanistic, translational and clinical research data, as well as a broad intellectual property portfolio on the therapeutic opportunities of CO for multiple diseases. For more information, please visit www.proterris.com.


Pena A.C.,University of Lisbon | Penacho N.,Alfama Lda | Mancio-Silva L.,University of Lisbon | Neres R.,University of Lisbon | And 9 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2012

Severe forms of malaria infection, such as cerebral malaria (CM) and acute lung injury (ALI), are mainly caused by the apicomplexan parasite Plasmodium falciparum. Primary therapy with quinine or artemisinin derivatives is generally effective in controlling P. falciparum parasitemia, but mortality from CM and other forms of severe malaria remains unacceptably high. Herein, we report the design and synthesis of a novel carbon monoxide-releasing molecule (CO-RM; ALF492) that fully protects mice against experimental CM (ECM) and ALI. ALF492 enables controlled CO delivery in vivo without affecting oxygen transport by hemoglobin, the major limitation in CO inhalation therapy. The protective effect is CO dependent and induces the expression of heme oxygenase-1, which contributes to the observed protection. Importantly, when used in combination with the antimalarial drug artesunate, ALF492 is an effective adjunctive and adjuvant treatment for ECM, conferring protection after the onset of severe disease. This study paves the way for the potential use of CO-RMs, such as ALF492, as adjunctive/adjuvant treatment in severe forms of malaria infection. Copyright © 2012, American Society for Microbiology. All Rights Reserved.


Rodrigues C.A.B.,Alfama Lda | De Matos M.N.,Alfama Lda | Guerreiro B.M.H.,Alfama Lda | Goncalves A.M.L.,Alfama Lda | And 3 more authors.
Tetrahedron Letters | Year: 2011

Decarbonylation of the tertiary aldehydes 4-ethyl-4-formyl-hexanenitrile (2) and 2-methyl-2-phenylpropanal (4) promoted by dioxygen occurs at room temperature only if suspended in water probably via the sequential acyl radical-CO liberation-tertiary radical that is promoted by an 'on water' process originating preferentially from the corresponding tertiary hydroperoxide. © 2011 Elsevier Ltd. All rights reserved.


Seixas J.D.,Alfama Lda | Mukhopadhyay A.,New University of Lisbon | Santos-Silva T.,New University of Lisbon | Otterbein L.E.,Beth Israel Deaconess Medical Center | And 11 more authors.
Dalton Transactions | Year: 2013

The complex fac-[Mo(CO)3(histidinate)]Na has been reported to be an effective CO-Releasing Molecule in vivo, eliciting therapeutic effects in several animal models of disease. The CO releasing profile of this complex in different settings both in vitro and in vivo reveals that the compound can readily liberate all of its three CO equivalents under biological conditions. The compound has low toxicity and cytotoxicity and is not hemolytic. CO release is accompanied by a decrease in arterial blood pressure following administration in vivo. We studied its behavior in solution and upon the interaction with proteins. Reactive oxygen species (ROS) generation upon exposure to air and polyoxomolybdate formation in soaks with lysozyme crystals were observed as processes ensuing from the decomposition of the complex and the release of CO. © 2013 This journal is The Royal Society of Chemistry.


Tavares A.F.N.,New University of Lisbon | Teixeira M.,New University of Lisbon | Romao C.C.,New University of Lisbon | Romao C.C.,Alfama Lda. | And 4 more authors.
Journal of Biological Chemistry | Year: 2011

CO-releasing molecules (CO-RMs) were previously shown by us to be more potent bactericides than CO gas. This suggests a mechanism of action for CO-RM, which either potentiates the activity of CO or uses another CO-RM-specific effect. We have also reported that CORM-2 induces the expression of genes related to oxidative stress. In the present study we intend to establish whether the generation of reactive oxygen species by CO-RMs may indeed result in the inhibition of bacterial cellular function. We now report that two CO-RMs (CORM-2 and ALF062) stimulate the production of ROS in Escherichia coli, an effect that is abolished by addition of antioxidants. Furthermore, deletion of genes encoding E. coli systems involved in reactive oxygen species scavenging, namely catalases and superoxide dismutases, potentiates the lethality of CORM-2 due to an increase of intracellular ROS content. CORM-2 also induces the expression of the E. coli DNA repair/SOS system recA, and its inactivation enhances toxicity of CORM-2. Moreover, fluorescence microscopy images reveal that CORM-2 causes DNA lesions to bacterial cells. We also demonstrate that cells treated with CORM-2 contain higher levels of free iron arising from destruction of iron-sulfur proteins. Importantly, we show that CO-RMs generate hydroxyl radicals in a cell-free solution, a process that is abolished by scavenging CO. Altogether, we provide a novel insight into the molecular basis of CO-RMs action by showing that their bactericidal properties are linked to cell damage inflicted by the oxidative stress that they are able to generate. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.


Santos M.F.A.,New University of Lisbon | Seixas J.D.,Alfama Lda | Seixas J.D.,New University of Lisbon | Coelho A.C.,New University of Lisbon | And 6 more authors.
Journal of Inorganic Biochemistry | Year: 2012

Complexes of the general formula fac-[Ru(CO)3L3] 2 +, namely CORM-2 and CORM-3, have been successfully used as experimental CO releasing molecules (CO-RMs) but their mechanism of action and delivery of CO remain unclear. The well characterized complex [Ru(CO) 3Cl2(1,3-thiazole)] (1) is now studied as a potential model CO-RM of the same family of complexes using LC-MS, FTIR, and UV-vis spectroscopy, together with X-ray crystallography. The chemistry of [Ru(CO) 3Cl2(1,3-thiazole)] is very similar to that of CORM-3: it only releases residual amounts of CO to the headspace of a solution in PBS7.4 and produces marginal increase of COHb after long incubation in whole blood. 1 also reacts with lysozyme to form Ru adducts. The crystallographic model of the lysozyme-Ru adducts shows only mono-carbonyl Ru species. [Ru(H 2O)4(CO)] is found covalently bound to a histidine (His15) and to two aspartates (Asp18 and Asp119) at the protein surface. The CO release silence of both 1 and CORM-3 and their rapid formation of protein-Ru(CO) x(H2O)y (x = 1,2) adducts, support our hypothesis that fac-[Ru(CO)3L3] CO-RMs deliver CO in vivo through the decay of their adducts with plasma proteins. © 2012 Elsevier Inc. All rights reserved.


Fagone P.,University of Catania | Mangano K.,University of Catania | Coco M.,University of Catania | Perciavalle V.,University of Catania | And 3 more authors.
Clinical and Experimental Immunology | Year: 2012

Carbon monoxide (CO) is produced during the catabolism of free haem, catalyzed by haem oxygenase (HO) enzymes, and its physiological roles include vasodilation, neurotransmission, inhibition of platelet aggregation and anti-proliferative effects on smooth muscle. In vivo preclinical studies have shown that exogenously administered quantities of CO may represent an effective treatment for conditions characterized by a dysregulated immune response. The carbon monoxide-releasing molecules (CORMs) represent a group of compounds capable of carrying and liberating controlled quantities of CO in the cellular systems. This review covers the physiological and anti-inflammatory properties of the HO/CO pathway in the central nervous system. It also discusses the effects of CORMs in preclinical models of inflammation. The accumulating data discussed herein support the possibility that CORMs may represent a novel class of drugs with disease-modifying properties in multiple sclerosis. © 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.


Santos-Silva T.,New University of Lisbon | Mukhopadhyay A.,New University of Lisbon | Seixas J.D.,New University of Lisbon | Seixas J.D.,Alfama Lda. | And 5 more authors.
Current Medicinal Chemistry | Year: 2011

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 but also intrinsic severe limitations. The possibility of replacing the gas by pro-drugs acting as CO-Releasing Molecules (CO-RMs) has clearly been demonstrated with several experimental compounds. Transition metal carbonyls complexes have proven to be the most versatile experimental 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 ADME profiles like the plasma proteins. In this account we analyze these questions and review the existing interactions between Metal Carbonyls and proteins. The recently explored case of CORM-3 is revisited to exemplify the methodologies involved and the importance of the results for the understanding of the mode of action of such pro-drugs. © 2011 Bentham Science Publishers Ltd.


Marazioti A.,University of Patras | Bucci M.,University of Naples Federico II | Coletta C.,University of Texas Medical Branch | Vellecco V.,University of Naples Federico II | And 11 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Objective-: Carbon monoxide (CO) is a weak soluble guanylyl cyclase stimulator, leading to transient increases in cGMP and vasodilation. The aim of the present work was to measure the effect of CO-releasing molecules (CORMs) on the cGMP/nitric oxide (NO) pathway and to evaluate how selected CORMs affect NO-induced vasorelaxation. Methods and Results-: Incubation of smooth muscle cells with some but not all of the CORMs caused a minor increase in cGMP levels. Concentration-response curves were bell-shaped, with higher CORMs concentrations producing lower increases in cGMP levels. Although exposure of cells to CORM-2 enhanced cGMP formation, we observed that the compound inhibited NO-stimulated cGMP accumulation in cells and NO-stimulated soluble guanylyl cyclase activity that could be reversed by superoxide anion scavengers. Reactive oxygen species generation from CORMs was confirmed using luminol-induced chemiluminescence and electron spin resonance. Furthermore, we observed that NO is scavenged by CORM-2. When used alone CORM-2 relaxed vessels through a cGMP-mediated pathway but attenuated NO donor-stimulated vasorelaxation. Conclusion-: We conclude that the CORMs examined have context-dependent effects on vessel tone, as they can directly dilate blood vessels, but also block NO-induced vasorelaxation. © 2011 American Heart Association. All rights reserved.


Santos-Silva T.,New University of Lisbon | Mukhopadhyay A.,New University of Lisbon | Seixas J.D.,New University of Lisbon | Seixas J.D.,Alfama Lda. | And 4 more authors.
Journal of the American Chemical Society | Year: 2011

CORM-3, [fac-Ru(CO)3Cl(κ2-H2NCH 2CO2)], is a well-known carbon monoxide releasing molecule (CORM) capable of delivering CO in vivo. Herein we show for the first time that the interactions of CORM-3 with proteins result in the loss of a chloride ion, glycinate, and one CO ligand. The rapid formation of stable adducts between the protein and the remaining cis-RuII(CO)2 fragments was confirmed by Inductively Coupled Plasma-Atomic Emission Spectrocopy (ICP-AES), Liquid-Chromatography Mass Spectrometry (LC-MS), Infrared Spectroscopy (IR), and X-ray crystallography. Three Ru coordination sites are observed in the structure of hen egg white lysozyme crystals soaked with CORM-3. The site with highest Ru occupancy (80%) shows a fac-[(His15)Ru(CO)2(H 2O)3] structure. © 2011 American Chemical Society.

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