Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

Addiction Treatment and Stable Housing among a Cohort of Injection Drug Users

Background: Unstable housing and homelessness is prevalent among injection drug users (IDU). We sought to examine whether accessing addiction treatment was associated with attaining stable housing in a prospective cohort of IDU in Vancouver, Canada. Methods: We used data collected via the Vancouver Injection Drug User Study (VIDUS) between December 2005 and April 2010. Attaining stable housing was defined as two consecutive ‘‘stable housing’ ’ designations (i.e., living in an apartment or house) during the follow-up period. We assessed exposure to addiction treatment in the interview prior to the attainment of stable housing among participants who were homeless or living in single room occupancy (SRO) hotels at baseline. Bivariate and multivariate associations between the baseline and time-updated characteristics and attaining stable housing were examined using Cox proportional hazard regression models. Principal Findings: Of the 992 IDU eligible for this analysis, 495 (49.9%) reported being homeless, 497 (50.1%) resided in SRO hotels, and 380 (38.3%) were enrolled in addiction treatment at the baseline interview. Only 211 (21.3%) attained stable housing during the follow-up period and of this group, 69 (32.7%) had addiction treatment exposure prior to achieving stable housing. Addiction treatment was inversely associated with attaining stable housing in a multivariate model (adjusted hazard ratio [AHR] = 0.71; 95 % CI: 0.52–0.96). Being in a partnered relationship was positively associated with the primary outcom

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

A significant challenge in chemistry is to rationally reproduce the functional potency of a protein in a small molecule, which is cheaper to manufacture, non-immunogenic, and also both stable and bioavailable. Synthetic peptides corresponding to small bioactive protein surfaces do not form stable structures in water and do not exhibit the functional potencies of proteins. Here we describe a novel approach to growing small molecules with protein-like potencies from a functionally important amino acid of a protein. A 77-residue human inflammatory protein (complement C3a) important in innate immunity is rationally transformed to equipotent small molecules, using peptide surrogates that incorporate a turn-inducing heterocycle with correctly positioned hydrogen-bond-accepting atoms. Small molecule agonists (molecular weigh

Impact of housing on the survival of persons with AIDS

<p>Abstract</p> <p>Background</p> <p>Homeless persons with HIV/AIDS have greater morbidity and mortality, more hospitalizations, less use of antiretroviral therapy, and worse medication adherence than HIV-infected persons who are stably housed. We examined the effect of homelessness on the mortality of persons with AIDS and measured the effect of supportive housing on AIDS survival.</p> <p>Methods</p> <p>The San Francisco AIDS registry was used to identify homeless and housed persons who were diagnosed with AIDS between 1996 and 2006. The registry was computer-matched with a housing database of homeless persons who received housing after their AIDS diagnosis. The Kaplan-Meier product limit method was used to compare survival between persons who were homeless at AIDS diagnosis and those who were housed. Proportional hazards models were used to estimate the independent effects of homelessness and supportive housing on survival after AIDS diagnosis.</p> <p>Results</p> <p>Of the 6,558 AIDS cases, 9.8% were homeless at diagnosis. Sixty-seven percent of the persons who were homeless survived five years compared with 81% of those who were housed (p < 0.0001). Homelessness increased the risk of death (adjusted relative hazard [RH] 1.20; 95% confidence limits [CL] 1.03, 1.41). Homeless persons with AIDS who obtained supportive housing had a lower risk of death than those who did not (adjusted RH 0.20; 95% CL 0.05, 0.81).</p> <p>Conclusion</p> <p>Supportive housing ameliorates the negative effect of homelessness on survival with AIDS.</p

Cardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party and collaborating partners.

Systemic sclerosis (SSc) is a rare disabling autoimmune disease with a similar mortality to many cancers. Two randomized controlled trials of autologous hematopoietic stem cell transplantation (AHSCT) for SSc have shown significant improvement in organ function, quality of life and long-term survival compared to standard therapy. However, transplant-related mortality (TRM) ranged from 3-10% in patients undergoing HSCT. In SSc, the main cause of non-transplant and TRM is cardiac related. We therefore updated the previously published guidelines for cardiac evaluation, which should be performed in dedicated centers with expertize in HSCT for SSc. The current recommendations are based on pre-transplant cardiopulmonary evaluations combining pulmonary function tests, echocardiography, cardiac magnetic resonance imaging and invasive hemodynamic testing, initiated at Northwestern University (Chicago) and subsequently discussed and endorsed within the EBMT ADWP in 2016

Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation

In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized

Designing supramolecular structures from models of cyclic peptide scaffolds with heterocyclic constraints

Cyclic peptides containing oxazole and thiazole heterocycles have been examined for their capacity to be used as scaffolds in larger, more complex, protein-like structures. Both the macrocyclic scaffolds and the supramolecular structures derived therefrom have been visualised by molecular modelling techniques. These molecules are too symmetrical to examine structurally by NMR spectroscopy. The cyclic hexapeptide ([Aaa-Thz](3), [Aaa-Oxz](3)) and cyclic octapeptide ([Aaa-Thz](4), [Aaa-Oxz](4)) analogues are composed of dipeptide surrogates (Aaa: amino acid, Thz: thiazole, Oxz: oxazole) derived from intramolecular condensation of cysteine or serine/threonine side chains in dipeptides like Aaa-Cys, Aaa-Ser and Aaa-Thr. The five-membered heterocyclic rings, like thiazole, oxazole and reduced analogues like thiazoline, thiazolidine and oxazoline have profound influences on the structures and bioactivities of cyclic peptides derived therefrom. This work suggests that such constrained cyclic peptides can be used as scaffolds to create a range of novel protein-like supramolecular structures (e.g. cylinders, troughs, cones, multi-loop structures, helix bundles) that are comparable in size, shape and composition to bioactive surfaces of proteins. They may therefore represent interesting starting points for the design of novel artificial proteins and artificial enzymes. (C) 2002 Elsevier Science Inc. All rights reserved