Antiviral polymeric drugs and surface coatings

Thesis (Ph. D. in Biological Chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013.Cataloged from PDF version of thesis. Vita.Includes bibliographical references.Viruses are a major cause of human morbidity and mortality in the world. New effective approaches to stop their spread are paramount. Herein, two approaches toward this goal are explored: (i) developing multivalent therapeutics (multiple copies of an antiviral agent covalently attached to a polymeric chain) with superior potency against their viral targets, and (ii) creating antiviral surface coatings that detoxify aqueous solutions containing various viruses on contact. By harnessing the power of multivalency we endeavored to improve the potency of influenza inhibitors, as well as resurrect the potency of two FDA-approved influenza inhibitors for which widespread drug resistance now exists. In the former direction of research, we attached multiple copies of bicyclic naphthoquinone-like monomeric inhibitors to polymeric chains. When tested against the Wuhan strain of influenza, these multivalent conjugates were up to 240- fold more potent inhibitors than their monomeric predecessors. However, this improvement in potency was strain-dependent, as two other serotypically-different influenza strains were not inhibited nearly as well by multivalent inhibitors. This strategy was also employed to restore inhibition for the adamantane class of influenza inhibitors against drug-resistant strains. The chemical modifications to the adamantane scaffold necessary for polymer attachment imposed deleterious steric constraints which resulted in poorer inhibitory effect. Even despite these drawbacks, however, the drug-polymer conjugates were up to 30-fold more potent against drug-resistant strains than their monomeric counterparts. These efforts made strides toward the ultimate goal of recovery of influenza virus inhibition for the adamantanes. To diminish transmission of viral infections, we explored the action of antimicrobial PEIbased (PEI = polyethylenimine) hydrophobic polycations against both enveloped and nonenveloped viruses. When solutions containing herpes simplex viruses (both 1 and 2) were brought in contact with NN-dodecyl,methyl-PEI coated on either polyethylene slides or latex condoms, they could be disinfected by up to 6-logs of viral titers. Our hydrophobic polycation also could be formulated into a suspension to disinfect herpes simplex virus-containing solutions, suggesting potential utility in a therapeutic modality. We also investigated whether these findings were applicable to non-enveloped viruses, namely poliovirus and rotavirus. Aqueous solutions containing them indeed could be drastically disinfected by our hydrophobic polycation-coated slides; subsequent mechanistic studies suggested that this disinfection was due to adsorption of the viruses onto the coated surfaces from solution.by Alyssa Maxine Larson.Ph.D.in Biological Chemistr

Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants

By attaching multiple copies of the influenza M2 ion channel inhibitors amantadine (1) and rimantadine (2) to polymeric chains, we endeavored to recover their potency in inhibiting drug-resistant influenza viruses. Depending on loading densities, as well as the nature of the drug, the polymer, and the spacer arm, polymer-conjugated drugs were up to 30-fold more potent inhibitors of drug-resistant strains than their monomeric parents. In particular, a 20% loading density and a short linker group on the negatively charged poly-l-glutamate resulted in one of the most potent inhibitors for 2's conjugates against drug-resistant influenza strains. Although full recovery of the inhibitory action against drug-resistant strains was not achieved, this study may be a step toward salvaging anti-influenza drugs that are no longer effective.Martin Family Society of Fellows for SustainabilityNational Institutes of Health (U.S.) (Grant U01-AI074443

Examining Occupational Therapists’ Role in Providing Client-Centered Care for School-Aged Children in the Educational Setting with Visual Impairment

In a foundational statement outlining the profession’s belief regarding the needs of the pediatric population with visual impairments, the American Occupational Therapy Association (AOTA) stated children with visual impairments “benefit significantly from coordinated and comprehensive services to enable them to learn to use their remaining vision more efficiently and use nonvisual methods to complete activities” (Warren & Nobles, 2011, p. 2). According to Warren and Nobles (2011), individuals can have two types of visual impairments: cortical visual impairment and ocular visual impairment. Cortical visual impairment (CVI) deals with affected areas of the brain that limits visual processing, whereas ocular visual impairment is specific to deficits affecting the eyes. CVIs are the leading cause of visual impairments. Since children with CVI have difficulties with visual processing, this can lead to a negative impact on their participation in education. Visual impairment can lead to a delay in the child’s learning and impact their developmental milestones. CVIs can also impair one’s ability to participate in other occupations such as playing, self-feeding, dressing, and navigating the environment (Harpster et al., 2022). According to Synder et al. (2019), 27,000 students with visual impairments receive services in U.S. school systems yearly. The current culture and environment of school settings present significant challenges for students with visual impairments; however, collaborative team efforts and skilled occupational services in the school system can maximize their success (Doxsey & Jones, 2021)

Antiviral and Antibacterial Polyurethanes of Various Modalities

We have prepared and characterized a new polyurethane-based antimicrobial material, N,N-dodecyl,methyl-polyurethane (Quat-12-PU). It exhibits strong antiviral and antibacterial activities when coated (as an organic solution or an aqueous nanosuspension) onto surfaces and antibacterial activity when electrospun into nanofibers. Quat-12-PU surfaces are able to kill airborne Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli bacteria, as well as inactivate the enveloped influenza virus (but not the non-enveloped poliovirus).United States. Army Research Office. Institute for Soldier NanotechnologiesMartin Family Society of Fellows for Sustainabilit

Decreasing Herpes Simplex Viral Infectivity in Solution by Surface-Immobilized and Suspended N,N-Dodecyl,methyl-polyethylenimine

Purpose To explore surface-immobilized and suspended modalities of the hydrophobic polycation N,N-dodecyl,methyl-polyethylenimine (DMPEI) for the ability to reduce viral infectivity in aqueous solutions containing herpes simplex viruses (HSVs) 1 and 2. Methods Surface-immobilized (coated onto surfaces) and suspended DMPEI were incubated with aqueous solutions containing HSV-1 or -2 to measure the antiviral effect of the hydrophobic polycation’s formulations on HSVs. Results DMPEI coated on either polyethylene slides or male latex condoms dramatically decreases infectivity in solutions containing HSV-1 or -2. Moreover, DMPEI suspended in aqueous solution markedly reduces the infectious titer of these HSVs. Conclusion Our results suggest potential uses of DMPEI for both prophylaxis (in the form of coated condoms) and treatment (as a topical suspension) for HSV infections.Martin Family Graduate FellowshipNational Institutes of Health (U.S.) (Grant AI057552)United States. Army Research Office (Grant W911NF-07-D-0004

Conjugating drug candidates to polymeric chains does not necessarily enhance anti-influenza activity

Using the plaque reduction assay, relatively simple bicyclic quinone molecules, as well as multiple copies thereof covalently attached to a long polyglutamate-based polymeric chain, were examined as new inhibitors of various naturally occurring strains of influenza A virus. The polymer-conjugated inhibitors were found to have a far greater potency (for some as high as two orders of magnitude when a long spacer arm was employed) than their corresponding parent molecules against the human Wuhan influenza strain. However, such polymeric inhibitors failed to exhibit higher potency compared with their small molecule predecessors against the human Puerto Rico and avian turkey influenza strains. These observations, further explored by means of molecular modeling, reveal the previously unrecognized unpredictability of the benefits of multivalency, possibly because of poor accessibility of the viral targets to polymeric agentsNational Institutes of Health (U.S.) (Grant U01-AI074443

Native Voices Rising: A Case for Funding Native-led Change

Native American organizations face enormous challenges to their communities, their lands and environment, and their basic rights as Indigenous peoples. They face these challenges with limited support from the broad spectrum of America's philanthropic institutions. Far too many foundations simply give little to nothing at all in support of Native causes, a situation that requires corrective action designed to close the enormous gap between foundation giving and the needs of Native communities. The low level of charitable foundation funding (.3%) going to Native causes, and the need to garner more support for Native organizing and advocacy work, in particular, prompted the Common Counsel Foundation and Native Americans in Philanthropy to jointly sponsor this research project that is focused on Native organizations which undergird the following five movements: Environmental Justice, Subsistence in Alaska, Native Engagement in the Urban Context, Media and Voter Engagement. The organizations varied considerably in experience and the methods they use to pursue change. They fulfill many roles in their respective communities, such as: advocates, organizers, service providers, and community builders. A key role is that they serve as places where people can acquire knowledge and skills that enable them to assume leadership roles in the organization and in the community. Leadership development is essential to maintaining and advancing these movements. Most importantly, Native self-determination and sovereignty is reinforced through the work of these organizations. To accomplish these goals, three sets of data were compiled. First, Native organizations in the targeted movements were contacted to obtain basic information that could be used to write brief thumbnail sketches about their organizations that included mission statements, current organizing and advocacy efforts, and contact information. Second, in-depth interviews were conducted with approximately 10 organizational leaders in each of the five movements to build a deeper understanding of how the organizations pursue their organizing and advocacy agendas, and seek change in their communities. Third, case studies of ten exemplary organizations, two in each movement, were compiled to illustrate the magnitude of the work. Representatives of 501(c)3 organizations, organizations using fiscal agents, and a few tribal governments and village councils participated in the study. In total, 146 organizations responded. Representatives from 49 of these organizations gave more intensive, in-depth interviews. Thumbnail sketches of all 146 organizations, the 10 case studies, as well as contextual information about each movement are contained in the full report

Hydrophobic Polycationic Coatings Disinfect Poliovirus and Rotavirus Solutions

Coating surfaces with N-alkylated polyethylenimines (PEIs), namely branched N,N-hexyl,methyl-PEI via covalent attachment to glass or linear N,N-dodecyl,methyl-PEI by physical deposition (“painting”) onto polyethylene, enables the resultant materials to quickly and efficiently disinfect aqueous solutions of (non-enveloped) poliovirus and rotavirus.United States. Army Research Office. (Grant Number DAAD-19-02-D0002)Tata Chemicals Limite

The Dynamics of Dense Cores in the Perseus Molecular Cloud II: The Relationship Between Dense Cores and the Cloud

We utilize the extensive datasets available for the Perseus molecular cloud to analyze the relationship between the kinematics of small-scale dense cores and the larger structures in which they are embedded. The kinematic measures presented here can be used in conjunction with those discussed in our previous work as strong observational constraints that numerical simulations (or analytic models) of star formation should match. We find that dense cores have small motions with respect to the 13CO gas, about one third of the 13CO velocity dispersion along the same line of sight. Within each extinction region, the core-to-core velocity dispersion is about half of the total (13CO) velocity dispersion seen in the region. Large-scale velocity gradients account for roughly half of the total velocity dispersion in each region, similar to what is predicted from large-scale turbulent modes following a power spectrum of P(k) ~ k^{-4}.Comment: Accepted for publication in ApJ. 47 pages (preprint format), 20 figures, 5 table

This Is Just A Test: Overcoming High-Stakes Test Anxiety through Relaxation and Gum Chewing When Preparing for the ACT

This study was a replication of a previous study (in which) participants were given relaxation and deep breathing training to help manage test anxiety. The study examined the correlations between relaxation strategies, gum chewing and variables including socioeconomic status, class rank, GPA, and importance of going to college. Participants included 96 high school students (36 males, 60 females), preparing for the ACT (American College Testing). Results indicated that the relaxation intervention had a significant effect in reducing test anxiety