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Polymer therapeutics is a class of (bio)hybrid materials that include a plethora of biologically active (synthetic) macromolecules that either consist of polymeric drugs, drug-polymer conjugates, peptide/protein-polymer conjugates or of drug, peptide or proteins covalently linked to self-assembled entities, such as polymer micelles and liposomes. Interest in polymer therapeutics has increased in the last decades particularly as anti-cancer therapeutics, influenza therapeutics, non-viral alternatives to gene delivery and in the advent of biological terrorism as anthrax inoculates. The human immunodeficiency virus (HIV) is one of the most deadly diseases known and despite improvement in education, preventative methods and drug therapies, the virus still affects approximately 33 million people worldwide. Classical therapeutics against HIV consist of low molecular weight drugs that inhibit various viral enzymes in the cell, including reverse transcriptase, integrase and protease. More recently, drugs that target the entry and fusion of the virus have formed a new class of inhibitors, some of which are effective (candidate) drugs. One of the fusion inhibitors that were approved is the drug T-20. T-20 is a 36-amino acid peptide derived from the heptad repeat 2 (HR2) of the HIV-1 glycoprotein gp41and acts as a competitive inhibitor by preventing the fusion of the viral and host cell membrane. Despite the effectiveness of T-20, one major drawback is associated with this drug namely low plasma lifetime. One of the goals of this Thesis is to design and synthesize effective HR2 derived fusion inhibitors through conjugation with synthetic polymers, while extending the lifetime. In addition, a novel concept for macromolecular HIV entry inhibition known as polyvalent inhibition is assessed in this Thesis. This Thesis consists of five chapters in which polymer therapeutics as carriers and polyvalent entities are explored against HIV-1. With the state of the art of HIV-1 therapeutics including polymer therapeutics summarized in Chapter 1, the remainder of the Thesis expands and defines the terrain with regard to novel (bio)hybrid materials as therapeutics against HIV-1. Very few polymer therapeutics that target HIV before cellular entry have been described. Even fewer polymer-based therapeutics inhibit HIV-1 entry via the specific interaction to the HIV-1 envelope proteins. In Chapter 2, novel polyvalent copolymers that specifically target the HIV-1 envelope protein gp120 were generated using a living polymerization technique known as ‘reversible addition-fragmentation chain transfer’ (RAFT), followed by a post-polymerization modification strategy. The strategy involves two synthetic steps, namely an ester/amide exchange followed by a thiol-ene addition of peptide ligands to generate a library of polyvalent copolymers, with varying peptide ligand, 2-hydroxypropyl methacrylamide and allyl methacrylamide content. These novel polyvalent polymers were shown to be effective HIV-1 entry inhibitors. Fusion inhibitors derived from the HR2 domain of gp41 such as T-20, act as competitive inhibitors by binding to the HR1 domain on the envelope glycoprotein gp41, which is involved in HIV-1 – host cell membrane fusion. However, the peptidic nature of these fusion inhibitors restricts their lifetime because they are prone to proteolytic degradation. Chapter 3 explores the effect of attaching synthetic polymer poly(ethylene glycol) (PEG) site-specifically to a HR2 derived peptide fusion inhibitor. The PEGylated peptides were assessed for their biophysical properties, efficacy as membrane fusion inhibitors and stability towards trypsin that was used as a model to show the effectiveness of the PEG to protect the peptide from proteolytic degradation. Although PEGylation causes a reduction in efficacy, this Chapter demonstrates that judicial PEGylation of the peptide can minimize the detrimental effects on inhibitory efficacy, while increasing lifetime against a protease. Conjugation of PEG and the site of PEG conjugation both have a profound effect on the efficacy of HR2 derived membrane fusion inhibitors. However, the effects on the mechanism of HIV-1 infectivity inhibition by polymer conjugated HR2 peptide inhibitors are not known. Chapter 4 investigates the effect of architecturally different synthetic linear PEG, v-shaped PEG or branched poly(glycerol) polymers conjugated to HR2 derived peptides. The peptide-polymer conjugates were then assessed for their inhibition efficacy, affinity and kinetics of binding towards a model of gp41, known as 5-Helix. The results indicate that attachment of a synthetic linear or branched polymer, despite causing a reduction in HIV-1 infectivity inhibition, does not significantly affect affinity towards 5-Helix. However, the rates of association and dissociation towards and from 5-Helix were reduced. Furthermore, synthetic polymer conjugation to HR2 derived peptides prolong their lifetime bound to gp41 and thus potentially reduces HIV-1 inhibition escape. Therefore, this Chapter demonstrates a previously unknown advantage of polymer conjugation to HIV-1 fusion peptide inhibitors. Chapter 5 systematically explores the modification of hydrophilic residues on the hydrophobic face of a HR2 derived peptide. The peptide mutants were assessed for their efficacy against membrane fusion inhibition as well as against fusion of HIV-1 wild type and T-20 resistant variants. Although the peptide mutants did not exhibit any improvement towards the inhibition of wild type membrane fusion, selected peptide mutants with point mutations were shown to be effective inhibitors towards T-20 resistant HIV-1 strains. In conclusion, peptide-polymer hybrid materials can make excellent candidates as long lasting therapeutics against wild type HIV-1 but also against emergent HIV-1 mutant variants. The knowledge from these Chapters will aid the design of innovative, next generation of peptide-polymer hybrid therapeutics.