Education & Certifications

  • Doctor of Philosophy, University of Madras, Chemistry-Bioorganic (2006)
  • Master of Science, University of Madras, Chemistry (1999)
  • Bachelor of Science, University of Madras, Chemistry (1995)


Work Experience

  • Research Associate/Scientist, Stanford University (December 2010 - Present)


    300 Pasteur drive, Stanford, CA 94305

  • Postdoctoral Scholar, University of California, Los Angeles (UCLA) (October 2006 - November 2010)


    635 Charles E. Young Drive south, Los Angeles, California

  • Ph.D Research Scholar, Bioorganic and Neurochemistry Laboratory, CLRI, CSIR. (2000 - 2006)

    University of Madras


    Adyar, Chennai, India.


Journal Articles

  • Transdermal deferoxamine prevents pressure-induced diabetic ulcers. Proceedings of the National Academy of Sciences of the United States of America Duscher, D., Neofytou, E., Wong, V. W., Maan, Z. N., Rennert, R. C., Inayathullah, M., Januszyk, M., Rodrigues, M., Malkovskiy, A. V., Whitmore, A. J., Walmsley, G. G., Galvez, M. G., Whittam, A. J., Brownlee, M., Rajadas, J., Gurtner, G. C. 2015; 112 (1): 94-99


    There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1?). In diabetes, HIF-1? function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1? transactivation. We examined whether local enhancement of HIF-1? activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1? activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1? transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.

    View details for DOI 10.1073/pnas.1413445112

    View details for PubMedID 25535360

  • [Pyr-1]-Apelin-13 delivery via nano-liposomal encapsulation attenuates pressure overload-induced cardiac dysfunction BIOMATERIALS Serpooshan, V., Sivanesan, S., Huang, X., Mahmoudi, M., Malkovskiy, A. V., Zhao, M., Inayathullah, M., Wagh, D., Zhang, X. J., Metzler, S., Bernstein, D., Wu, J. C., Ruiz-Lozano, P., Rajadas, J. 2015; 37: 289-298


    Nanoparticle-mediated sustained delivery of therapeutics is one of the highly effective and increasingly utilized applications of nanomedicine. Here, we report the development and application of a drug delivery system consisting of polyethylene glycol (PEG)-conjugated liposomal nanoparticles as an efficient inávivo delivery approach for [Pyr1]-apelin-13 polypeptide. Apelin is an adipokine that regulates a variety of biological functions including cardiac hypertrophy and hypertrophy-induced heart failure. The clinical use of apelin has been greatly impaired by its remarkably short half-life in circulation. Here, we investigate whether [Pyr1]-apelin-13 encapsulation in liposome nanocarriers, conjugated with PEG polymer on their surface, can prolong apelin stability in the blood stream and potentiate apelin beneficial effects in cardiac function. Atomic force microscopy and dynamic light scattering were used to assess the structure and size distribution of drug-laden nanoparticles. [Pyr1]-apelin-13 encapsulation in PEGylated liposomal nanocarriers resulted in sustained and extended drug release both inávitro and inávivo. Moreover, intraperitoneal injection of [Pyr1]-apelin-13 nanocarriers in a mouse model of pressure-overload induced heart failure demonstrated a sustainable long-term effect of [Pyr1]-apelin-13 in preventing cardiac dysfunction. We concluded that this engineered nanocarrier system can serve as a delivery platform for treating heart injuries through sustained bioavailability of cardioprotective therapeutics.

    View details for DOI 10.1016/j.biomaterials.2014.08.045

    View details for Web of Science ID 000346541100028

    View details for PubMedID 25443792

  • Borreliacidal activity of Borrelia metal transporter A (BmtA) binding small molecules by manganese transport inhibition DRUG DESIGN DEVELOPMENT AND THERAPY Wagh, D., Pothineni, V. R., Inayathullah, M., Liu, S., Kim, K., Rajadas, J. 2015; 9: 805-815


    Borrelia burgdorferi, the causative agent of Lyme disease, utilizes manganese (Mn) for its various metabolic needs. We hypothesized that blocking Mn transporter could be a possible approach to inhibit metabolic activity of this pathogen and eliminate the infection. We used a combination of in silico protein structure prediction together with molecular docking to target the Borrelia metal transporter A (BmtA), a single known Mn transporter in Borrelia and screened libraries of FDA approved compounds that could potentially bind to the predicted BmtA structure with high affinity. Tricyclic antihistamines such as loratadine, desloratadine, and 3-hydroxydesloratadine as well as yohimbine and tadalafil demonstrated a tight binding to the in silico folded BmtA transporter. We, then, tested borreliacidal activity and dose response of the shortlisted compounds from this screen using a series of in vitro assays. Amongst the probed compounds, desloratadine exhibited potent borreliacidal activity in vitro at and above 78 ?g/mL (250 ?M). Borrelia treated with lethal doses of desloratadine exhibited a significant loss of intracellular Mn specifically and a severe structural damage to the bacterial cell wall. Our results support the possibility of developing a novel, targeted therapy to treat Lyme disease by targeting specific metabolic needs of Borrelia.

    View details for DOI 10.2147/DDDT.S77063

    View details for Web of Science ID 000349239100003

    View details for PubMedID 25709405

  • Polymeric Nanoparticles to Combat Squamous Cell Carcinomas in Patients with Dystrophic Epidermolysis Bullosa. Recent patents on nanomedicine Manoukian, M. A., Ott, S. V., Rajadas, J., Inayathullah, M. 2014; 4 (1): 15-24


    Skin cancer is the leading cause of malignancy in the United States, with Basal Cell Carcinoma, Squamous Cell Carcinoma , and Melanoma being the three most common diagnoses, respectively. Squamous Cell Carcinoma (SCC) is a particular concern for patients suffering from Dystrophic Epidermolysis Bullosa (DEB), a disease that affects the production and function of collagen VII, a protein that forms the anchoring fibrils which bind the epidermis to the dermis. Patients with DEB suffer from chronic blistering and wounds that have impaired healing capabilities, often leading to the development of SCC and eventual mortality. Nanomedicine is playing an increasing role in the delivery of effective therapeutics to combat a wide range of diseases, including the imaging and treatment of SCC. In this review, we discuss the role of nanoparticles in the treatment of SCC with an emphasis on PLGA nanoparticles and SCCs found in patients suffering from DEB, and address recent patents that are pertinent to the development of novel nanomedical therapeutics.

    View details for PubMedID 25506404

  • Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Science translational medicine Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Qian, J., Dhillon, G., Gera, L., Farkas, L., Rabinovitch, M., Zamanian, R. T., Inayathullah, M., Fridlib, M., Rajadas, J., Peters-Golden, M., Voelkel, N. F., Nicolls, M. R. 2013; 5 (200): 200ra117-?


    Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease-associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting.

    View details for DOI 10.1126/scitranslmed.3006674

    View details for PubMedID 23986401

  • Polyvinylpyrrolidone microneedles enable delivery of intact proteins for diagnostic and therapeutic applications ACTA BIOMATERIALIA Sun, W., Araci, Z., Inayathullah, M., Manickam, S., Zhang, X., Bruce, M. A., Marinkovich, M. P., Lane, A. T., Milla, C., Rajadas, J., Butte, M. J. 2013; 9 (8): 7767-7774


    We present a method of fabricating microneedles from polyvinylpyrrolidone (PVP) that enables delivery of intact proteins (or peptides) to the dermal layers of the skin. PVP is known to self-assemble into branched hollow fibers in aqueous and alcoholic solutions; we utilized this property to develop dissolvable patches of microneedles. Proteins were dissolved in concentrated PVP solution in both alcohol and water, poured into polydimethylsiloxane templates shaped as microneedles and, upon evaporation of solvent, formed into concentric, fibrous, layered structures. This approach of making PVP microneedles overcomes problems in dosage, uniform delivery and stability of protein formulation as compared to protein-coated metallic microneedles or photopolymerized PVP microneedles. Here we characterize the PVP microneedles and measure the delivery of proteins into skin. We show that our method of fabrication preserves the protein conformation. These microneedles can serve as a broadly useful platform for delivering protein antigens and therapeutic proteins to the skin, for example for allergen skin testing or immunotherapy.

    View details for DOI 10.1016/j.actbio.2013.04.045

    View details for Web of Science ID 000322207700017

  • Solvent microenvironments and copper binding alters the conformation and toxicity of a prion fragment. PloS one Inayathullah, M., Satheeshkumar, K. S., Malkovskiy, A. V., Carre, A. L., Sivanesan, S., Hardesty, J. O., Rajadas, J. 2013; 8 (12)


    The secondary structures of amyloidogenic proteins are largely influenced by various intra and extra cellular microenvironments and metal ions that govern cytotoxicity. The secondary structure of a prion fragment, PrP(111-126), was determined using circular dichroism (CD) spectroscopy in various microenvironments. The conformational preferences of the prion peptide fragment were examined by changing solvent conditions and pH, and by introducing external stress (sonication). These physical and chemical environments simulate various cellular components at the water-membrane interface, namely differing aqueous environments and metal chelating ions. The results show that PrP(111-126) adopts different conformations in assembled and non-assembled forms. Aging studies on the PrP(111-126) peptide fragment in aqueous buffer demonstrated a structural transition from random coil to a stable ?-sheet structure. A similar, but significantly accelerated structural transition was observed upon sonication in aqueous environment. With increasing TFE concentrations, the helical content of PrP(111-126) increased persistently during the structural transition process from random coil. In aqueous SDS solution, PrP(111-126) exhibited ?-sheet conformation with greater ?-helical content. No significant conformational changes were observed under various pH conditions. Addition of Cu(2+) ions inhibited the structural transition and fibril formation of the peptide in a cell free in vitro system. The fact that Cu(2+) supplementation attenuates the fibrillar assemblies and cytotoxicity of PrP(111-126) was witnessed through structural morphology studies using AFM as well as cytotoxicity using MTT measurements. We observed negligible effects during both physical and chemical stimulation on conformation of the prion fragment in the presence of Cu(2+) ions. The toxicity of PrP(111-126) to cultured astrocytes was reduced following the addition of Cu(2+) ions, owing to binding affinity of copper towards histidine moiety present in the peptide.

    View details for DOI 10.1371/journal.pone.0085160

    View details for PubMedID 24386462

  • Enhanced A▀(1-40) production in endothelial cells stimulated with fibrillar A▀(1-42). PloS one Rajadas, J., Sun, W., Li, H., Inayathullah, M., Cereghetti, D., Tan, A., de Mello Coelho, V., Chrest, F. J., Kusiak, J. W., Smith, W. W., Taub, D., Wu, J. C., Rifkind, J. M. 2013; 8 (3)


    Amyloid accumulation in the brain of Alzheimer's patients results from altered processing of the 39- to 43-amino acid amyloid ? protein (A?). The mechanisms for the elevated amyloid (A?(1-42)) are considered to be over-expression of the amyloid precursor protein (APP), enhanced cleavage of APP to A?, and decreased clearance of A? from the central nervous system (CNS). We report herein studies of A? stimulated effects on endothelial cells. We observe an interesting and as yet unprecedented feedback effect involving A?(1-42) fibril-induced synthesis of APP by Western blot analysis in the endothelial cell line Hep-1. We further observe an increase in the expression of A?(1-40) by flow cytometry and fluorescence microscopy. This phenomenon is reproducible for cultures grown both in the presence and absence of serum. In the former case, flow cytometry reveals that A?(1-40) accumulation is less pronounced than under serum-free conditions. Immunofluorescence staining further corroborates these observations. Cellular responses to fibrillar A?(1-42) treatment involving eNOS upregulation and increased autophagy are also reported.

    View details for DOI 10.1371/journal.pone.0058194

    View details for PubMedID 23505467

  • Glucose Oxidase Incorporated Collagen Matrices for Dermal Wound Repair in Diabetic Rat Models: A Biochemical Study JOURNAL OF BIOMATERIALS APPLICATIONS Arul, V., Masilamoni, J. G., Jesudason, E. P., Jaji, P. J., Inayathullah, M., John, D. G., Vignesh, S., Jayakumar, R. 2012; 26 (8): 917-938


    Impaired wound healing in diabetes is a well-documented phenomenon. Emerging data favor the involvement of free radicals in the pathogenesis of diabetic wound healing. We investigated the beneficial role of the sustained release of reactive oxygen species (ROS) in diabetic dermal wound healing. In order to achieve the sustained delivery of ROS in the wound bed, we have incorporated glucose oxidase in the collagen matrix (GOIC), which is applied to the healing diabetic wound. Our in vitro proteolysis studies on incorporated GOIC show increased stability against the proteases in the collagen matrix. In this study, GOIC film and collagen film (CF) are used as dressing material on the wound of streptozotocin-induced diabetic rats. A significant increase in ROS (p?

    View details for DOI 10.1177/0885328210390402

    View details for Web of Science ID 000303649700002

    View details for PubMedID 21363874

  • Pullulan Hydrogels Improve Mesenchymal Stem Cell Delivery into High-Oxidative-Stress Wounds MACROMOLECULAR BIOSCIENCE Wong, V. W., Rustad, K. C., Glotzbach, J. P., Sorkin, M., Inayathullah, M., Major, M. R., Longaker, M. T., Rajadas, J., Gurtner, G. C. 2011; 11 (11): 1458-1466


    Cell-based therapies for wound repair are limited by inefficient delivery systems that fail to protect cells from the acute inflammatory environment. Here, a biomimetic hydrogel system is described that is based on the polymer pullulan, a carbohydrate glucan known to exhibit potent antioxidant capabilities. It is shown that pullulan hydrogels are an effective cell delivery system and improve mesenchymal stem cell survival and engraftment in high-oxidative-stress environments. The results suggest that glucan hydrogel systems may prove beneficial for progenitor-cell-based approaches to skin regeneration.

    View details for DOI 10.1002/mabi.201100180

    View details for Web of Science ID 000297555500002

    View details for PubMedID 21994074

  • Structural dynamics of the Delta E22 (Osaka) familial Alzheimer's disease-linked amyloid beta-protein AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS Inayathullah, M., Teplow, D. B. 2011; 18 (3): 98-107


    A familial form of Alzheimer disease recently was described in a kindred in Osaka, Japan. This kindred possesses an amyloid ?-protein (A?) precursor mutation within the A? coding region that results in the deletion of Glu22 (?E22). We report here results of studies of [?E22]A?40 and [?E22]A?42 that sought to elucidate the conformational dynamics, oligomerization behavior, fibril formation kinetics, fibril morphology, and fibril stability of these mutant peptides. Both [?E22]A? peptides had extraordinary ?-sheet formation propensities. The [?E22]A?40 mutant formed ?-sheet secondary structure elements ?400-fold faster. Studies of ?-sheet stability in the presence of fluorinated alcohol cosolvents or high pH revealed that the ?E22 mutation substantially increased stability, producing a rank order of [?E22]A?42 >A?42 > [?E22]A?40 > A?40. The mutation facilitated formation of oligomers by [?E22]A?42 (dodecamers and octadecamers) that were not observed with A?42. Both A?40 and A?42 peptides formed nebulous globular and small string-like structures immediately upon solvation from lyophilizates, whereas short protofibrillar and fibrillar structures were evident immediately in the ?E22 samples. Determination of the critical concentration for fibril formation for the [?E22]A? peptides showed it to be ?1/2 that of the wild type homologues, demonstrating that the mutations causes a modest increase in fibril stability. The magnitude of this increase, when considered in the context of the extraordinary increase in ?-sheet propensity for the ?E22 peptides, suggests that the primary biophysical effect of the mutation is to accelerate conformational changes in the peptide monomer that facilitate oligomerization and higher-order assembly.

    View details for DOI 10.3109/13506129.2011.580399

    View details for Web of Science ID 000294117300003

    View details for PubMedID 21668291

  • Rationally Designed Turn Promoting Mutation in the Amyloid-beta Peptide Sequence Stabilizes Oligomers in Solution PLOS ONE Rajadas, J., Liu, C. W., Novick, P., Kelley, N. W., Inayathullah, M., LeMieux, M. C., Pande, V. S. 2011; 6 (7)


    Enhanced production of a 42-residue beta amyloid peptide (A?(42)) in affected parts of the brain has been suggested to be the main causative factor for the development of Alzheimer's Disease (AD). The severity of the disease depends not only on the amount of the peptide but also its conformational transition leading to the formation of oligomeric amyloid-derived diffusible ligands (ADDLs) in the brain of AD patients. Despite being significant to the understanding of AD mechanism, no atomic-resolution structures are available for these species due to the evanescent nature of ADDLs that hinders most structural biophysical investigations. Based on our molecular modeling and computational studies, we have designed Met35Nle and G37p mutations in the A?(42) peptide (A?(42)Nle35p37) that appear to organize A?(42) into stable oligomers. 2D NMR on the A?(42)Nle35p37 peptide revealed the occurrence of two ?-turns in the V24-N27 and V36-V39 stretches that could be the possible cause for the oligomer stability. We did not observe corresponding NOEs for the V24-N27 turn in the A?(21-43)Nle35p37 fragment suggesting the need for the longer length amyloid peptide to form the stable oligomer promoting conformation. Because of the presence of two turns in the mutant peptide which were absent in solid state NMR structures for the fibrils, we propose, fibril formation might be hindered. The biophysical information obtained in this work could aid in the development of structural models for toxic oligomer formation that could facilitate the development of therapeutic approaches to AD.

    View details for DOI 10.1371/journal.pone.0021776

    View details for Web of Science ID 000293097300006

    View details for PubMedID 21799748

  • Efficient gene delivery of primary human cells using peptide linked polyethylenimine polymer hybrid BIOMATERIALS Dey, D., Inayathullah, M., Lee, A. S., LeMieux, M. C., Zhang, X., Wu, Y., Nag, D., De Almeida, P. E., Han, L., Rajadas, J., Wu, J. C. 2011; 32 (20): 4647-4658


    Polyethylenimine (PEI) based polymers are efficient agents for cell transfection. However, their use has been hampered due to high cell death associated with transfection thereby resulting in low efficiency of gene delivery within the cells. To circumvent the problem of cellular toxicity, metal binding peptides were linked to PEI. Eight peptide-PEI derivatives were synthesized to improve cell survival and transfection efficiency. TAT linked PEI was used as a control polymer. Peptides linked with PEI amines formed nanogels as shown by electron microscopy and atomic force microscopic measurements. Polymers were characterized by spectroscopic methods and their ability to form complexes with plasmids was tested using electrophoretic studies. These modifications improved polymer biocompatibility as well as cell survival markedly, when compared to PEI alone. A subset of the modified peptide-polymers also showed significantly higher transfection efficiency in primary human cells with respect to the widely used transfection agent, lipofectamine. Study of the underlying mechanism of the observed phenomena revealed lower levels of 'reactive oxygen species' (ROS) in the presence of the peptide-polymers when compared to PEI alone. This was further corroborated with global gene expression analysis which showed upregulation of multiple genes and pathways involved in regulating intracellular oxidative stress.

    View details for DOI 10.1016/j.biomaterials.2011.03.016

    View details for Web of Science ID 000291193700019

    View details for PubMedID 21477858

  • Amino Acid Position-specific Contributions to Amyloid beta-Protein Oligomerization JOURNAL OF BIOLOGICAL CHEMISTRY Maji, S. K., Loo, R. R., Inayathullah, M., Spring, S. M., Vollers, S. S., Condron, M. M., Bitan, G., Loo, J. A., Teplow, D. B. 2009; 284 (35): 23580-23591


    Understanding the structural and assembly dynamics of the amyloid beta-protein (Abeta) has direct relevance to the development of therapeutic agents for Alzheimer disease. To elucidate these dynamics, we combined scanning amino acid substitution with a method for quantitative determination of the Abeta oligomer frequency distribution, photo-induced cross-linking of unmodified proteins (PICUP), to perform "scanning PICUP." Tyr, a reactive group in PICUP, was substituted at position 1, 10, 20, 30, or 40 (for Abeta40) or 42 (for Abeta42). The effects of these substitutions were probed using circular dichroism spectroscopy, thioflavin T binding, electron microscopy, PICUP, and mass spectrometry. All peptides displayed a random coil --> alpha/beta --> beta transition, but substitution-dependent alterations in assembly kinetics and conformer complexity were observed. Tyr(1)-substituted homologues of Abeta40 and Abeta42 assembled the slowest and yielded unusual patterns of oligomer bands in gel electrophoresis experiments, suggesting oligomer compaction had occurred. Consistent with this suggestion was the observation of relatively narrow [Tyr(1)]Abeta40 fibrils. Substitution of Abeta40 at the C terminus decreased the population conformational complexity and substantially extended the highest order of oligomers observed. This latter effect was observed in both Abeta40 and Abeta42 as the Tyr substitution position number increased. The ability of a single substitution (Tyr(1)) to alter Abeta assembly kinetics and the oligomer frequency distribution suggests that the N terminus is not a benign peptide segment, but rather that Abeta conformational dynamics and assembly are affected significantly by the competition between the N and C termini to form a stable complex with the central hydrophobic cluster.

    View details for DOI 10.1074/jbc.M109.038133

    View details for Web of Science ID 000269180000044

    View details for PubMedID 19567875

  • Synthesis, pharmacological screening, quantum chemical and in vitro permeability studies of N-Mannich bases of benzimidazoles through bovine cornea EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Jesudason, E. P., Sridhar, S. K., Malar, E. J., Shanmugapandiyan, P., Inayathullah, M., Arul, V., Selvaraj, D., Jayakumar, R. 2009; 44 (5): 2307-2312


    A novel series of N-Mannich bases of benzimidazole derivatives were synthesized and characterized by (1)H NMR, IR spectral studies and elemental analysis. The compounds were screened for analgesic and anti-inflammatory activity. 1-((Diethylamino)-methyl)-2-styryl benzimidazole 4 at 40mg/kg was found to be equipotent to paracetamol. 1-((Piperidin-1-yl) methyl)-2-styryl-benzimidazole 6 at 40mg/kg was found to be more potent than Diclofenac. Corneal permeability and quantum chemical calculations were performed to correlate the hydrogen bonding ability with permeability and activity. The energies of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were correlated with pharmacological activity. The semi-empirical PM3 calculations (quantum chemical calculations) revealed that E(LUMO) and energy gap DeltaE were capable of accounting for the high in vitro bovine corneal permeability and activity of the compounds.

    View details for DOI 10.1016/j.ejmech.2008.03.043

    View details for Web of Science ID 000265339900062

    View details for PubMedID 18486995

  • Conformational polymorphism and cellular toxicity of IAPP and beta AP domains JOURNAL OF STRUCTURAL BIOLOGY Andrews, M. E., Inayathullah, N. M., Jayakumar, R., Malar, E. J. 2009; 166 (2): 116-125


    The principal component of the amyloid deposits in Alzheimer's disease is the beta-amyloid polypeptide, while in type II diabetes the deposits consist primarily of Islet amyloid polypeptide. These amyloid forming polypeptides consist of highly polymorphic domains, which take different conformations including random coil, helical and beta strand depending upon the microenvironment. We have studied major fibril-forming components of IAPP and beta AP and demonstrated that conformational polymorphism of these peptides in different microenvironments correlate with cellular toxicity and proteasomal inhibitory activity. On treating with trifluoroethanol (TFE) the peptide fragments undergo structural transition from a random coil to a helical conformation. Even though these domains share the same gross amyloid structural characteristic, their proteasomal activities differ. We found that even the tetrapeptides have significant proteasomal inhibitory activity indicating that the amyloid formation is involved in the enhanced life of the smaller aggregates of full-length and fragment peptides, which could explain the toxicity of these sequences.

    View details for DOI 10.1016/j.jsb.2008.12.011

    View details for Web of Science ID 000265560900002

    View details for PubMedID 19374013

  • Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy ACTA NEUROPATHOLOGICA Zaghi, J., Goldenson, B., Inayathullah, M., Lossinsky, A. S., Masoumi, A., Avagyan, H., Mahanian, M., Bernas, M., Weinand, M., Rosenthal, M. J., Espinosa-Jeffrey, A., de Vellis, J., Teplow, D. B., Fiala, M. 2009; 117 (2): 111-124


    Neuronal accumulation of oligomeric amyloid-beta (Alphabeta) is considered the proximal cause of neuronal demise in Alzheimer disease (AD) patients. Blood-borne macrophages might reduce Abeta stress to neurons by immigration into the brain and phagocytosis of Alphabeta. We tested migration and export across a blood-brain barrier model, and phagocytosis and clearance of Alphabeta by AD and normal subjects' macrophages. Both AD and normal macrophages were inhibited in Alphabeta export across the blood-brain barrier due to adherence of Abeta-engorged macrophages to the endothelial layer. In comparison to normal subjects' macrophages, AD macrophages ingested and cleared less Alphabeta, and underwent apoptosis upon exposure to soluble, protofibrillar, or fibrillar Alphabeta. Confocal microscopy of stained AD brain sections revealed oligomeric Abeta in neurons and apoptotic macrophages, which surrounded and infiltrated congophilic microvessels, and fibrillar Abeta in plaques and microvessel walls. After incubation with AD brain sections, normal subjects' monocytes intruded into neurons and uploaded oligomeric Abeta. In conclusion, in patients with AD, macrophages appear to shuttle Abeta from neurons to vessels where their apoptosis may release fibrillar Abeta, contributing to cerebral amyloid angiopathy.

    View details for DOI 10.1007/s00401-008-0481-0

    View details for Web of Science ID 000262784500002

    View details for PubMedID 19139910

  • Amyloid beta-Protein Assembly as a Therapeutic Target of Alzheimer's Disease CURRENT PHARMACEUTICAL DESIGN Yamin, G., Ono, K., Inayathullah, M., Teplow, D. B. 2008; 14 (30): 3231-3246


    Alzheimer's disease (AD), the most common neurodegenerative disorder in the aged, is characterized by the cerebral deposition of fibrils formed by the amyloid beta-protein (Abeta), a 40-42 amino acid peptide. The folding of Abeta into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathologic event in AD. Abeta is formed through cleavage of the Abeta precursor protein by two endoproteinases, beta-secretase and gamma-secretase, that cleave the Abeta N-terminus and C-terminus, respectively. These facts support the relevance of therapeutic strategies targeting Abeta production, assembly, clearance, and neurotoxicity. Currently, no disease-modifying therapeutic agents are available for AD patients. Instead, existing therapeutics provide only modest symptomatic benefits for a limited time. We summarize here recent efforts to produce therapeutic drugs targeting Abeta assembly. A number of approaches are being used in these efforts, including immunological, nutraceutical, and more classical medicinal chemical (peptidic inhibitors, carbohydrate-containing compounds, polyamines, "drug-like" compounds, chaperones, metal chelators, and osmolytes), and many of these have progressed to phase III clinical trails. We also discuss briefly a number of less mature, but intriguing, strategies that have therapeutic potential. Although initial trials of some disease-modifying agents have failed, we argue that substantial cause for optimism exists.

    View details for Web of Science ID 000261916000004

    View details for PubMedID 19075703

  • Isolation and partial characterization of antifungal protein from Bacillus polymyxa strain VLB16 PROCESS BIOCHEMISTRY Kavitha, S., Senthilkumar, S., Gnanamanickam, S., Inayathullah, M., Jayakumar, R. 2005; 40 (10): 3236-3243
  • Effect of osmolyte on the micellization of SDS at different temperatures LANGMUIR Inayathullah, N. M., Jasmine, G. J., Jayakumar, R. 2003; 19 (22): 9545-9547

    View details for DOI 10.1021/la034403z

    View details for Web of Science ID 000186177200068

  • Effect of Ca2+ on the self assembly of a nonionic peptide aggregate LETTERS IN PEPTIDE SCIENCE Moses, J. P., Inayathullah, N. M., Murugesan, M., Andrews, M. E., Balasubramanian, M. P., Jayakumar, R. 2003; 10 (1): 25-32

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