Aug
13
Tue
2013
Plenary Address: Making sense of pathogen sensors of Innate Immunity: Utility of their ligands as antiviral agens and adjuvants for vaccines. @ Acharya Hall
Aug 13 @ 9:17 am – 9:55 am

SuryaprakashSuryaprakash Sambhara, DVM, Ph.D
Chief, Immunology Section, Influenza Division, CDC, Atlanta, USA


Making sense of pathogen sensors of Innate Immunity: Utility of their ligands as antiviral agents and adjuvants for vaccines.

Currently used antiviral agents act by inhibiting viral entry, replication, or release of viral progeny.  However, recent emergence of drug-resistant viruses has become a major public health concern as it is limiting our ability to prevent and treat viral diseases.  Furthermore, very few antiviral agents with novel modes of action are currently in development.  It is well established that the innate immune system is the first line of defense against invading pathogens.  The recognition of diverse pathogen-associated molecular patterns (PAMPs) is accomplished by several classes of pattern recognition receptors (PRRs) and the ligand/receptor interactions trigger an effective innate antiviral response.  In the past several years, remarkable progress has been made towards understanding both the structural and functional nature of PAMPs and PRRs.  As a result of their indispensable role in virus infection, these ligands have become potential pharmacological agents against viral infections.  Since their pathways of action are evolutionarily conserved, the likelihood of viruses developing resistance to PRR activation is diminished.  I will discuss the recent developments investigating the potential utility of the ligands of innate immune receptors as antiviral agents and molecular adjuvants for vaccines.

Suryaprakash (1) Suryaprakash (4) Suryaprakash-Nagaraja

Invited Talk: Nanoscale Simulations – Tackling Form and Formulation Challenges in Drug Development and Drug Delivery @ Sathyam Hall
Aug 13 @ 2:15 pm – 2:40 pm

lalithaLalitha Subramanian, Ph.D.
Chief Scientific Officer & VP, Services at Scienomics, USA


Nanoscale Simulations – Tackling Form and Formulation Challenges in Drug Development and Drug Delivery

Lalitha Subramanian, Dora Spyriouni, Andreas Bick, Sabine Schweizer, and Xenophon Krokidis Scienomics

The discovery of a compound which is potent in activity against a target is a major milestone in Pharmaceutical and Biotech industry. However, a potent compound is only effective as a therapeutic agent when it can be administered such that the optimal quantity is transported to the site of action at an optimal rate. The active pharmaceutical ingredient (API) has to be tested for its physicochemical properties before the appropriate dosage form and formulation can be designed. Some of the commonly evaluated parameters are crystal forms and polymorphs, solubility, dissolution behavior, stability, partition coefficient, water sorption behavior, surface properties, particle size and shape, etc. Pharmaceutical development teams face the challenge of quickly and efficiently determining a number of properties with small quantities of the expensive candidate compounds. Recently the trend has been to screen these properties as early as possible and often the candidate compounds are not available in sufficient quantities. Increasingly, these teams are leveraging nanoscale simulations similar to those employed by drug discovery teams for several decades. Nanoscale simulations are used to predict the behavior using very little experimental data and only if this is promising further experiments are done. Another aspect where nanoscale simulations are being used in drug development and drug delivery is to get insights into the behavior of the system so that process failures can be remediated and formulation performance can be improved. Thus, the predictive screening and the in-depth understanding leads to experimental efficiency resulting in far-reaching business impacts.

With specific examples, this talk will focus on the different types of nanoscale simulations used to predict properties of the API in excipients and also provide insight into system behavior as a function of shelf life, temperature, mechanical stress, etc.

Aug
14
Wed
2013
Plenary Talk: Combined Crystallography and SAXS Methods for Studying Macromolecular Complexes @ Amriteshwari Hall
Aug 14 @ 9:38 am – 10:19 am

JeffPerryJeff Perry, Ph.D.
Assistant Professor, University of California, Riverside


Combined Crystallography and SAXS Methods for Studying Macromolecular Complexes

Recent developments in small angle X-ray scattering (SAXS) are rapidly providing new insights into protein interactions, complexes and conformational states in solution, allowing for detailed biophysical quantification of samples of interest1. Initial analyses provide a judgment of sample quality, revealing the potential presence of aggregation, the overall extent of folding or disorder, the radius of gyration, maximum particle dimensions and oligomerization state. Structural characterizations may include ab initio approaches from SAXS data alone, or enhance structural solutions when combined with previously determined crystal/NMR domains. This combination can provide definitions of architectures, spatial organizations of the protein domains within a complex, including those not yet determined by crystallography or NMR, as well as defining key conformational states. Advantageously, SAXS is not generally constrained by macromolecule size, and rapid collection of data in a 96-well plate format provides methods to screen sample conditions. Such screens include co-factors, substrates, differing protein or nucleotide partners or small molecule inhibitors, to more fully characterize the variations within assembly states and key conformational changes. These analyses are also useful for screening constructs and conditions that are most likely to promote crystal growth. Moreover, these high throughput structural determinations can be leveraged to define how polymorphisms affect assembly formations and activities. Also, SAXS-based technologies may be potentially used for novel structure-based screening, for compounds inducing shape changes or associations/diassociations. This is addition to defining architectural characterizations of complexes and interactions for systems biology-based research, and distinctions in assemblies and interactions in comparative genomics. Thus, SAXS combined with crystallography/NMR and computation provides a unique set of tools that should be considered as being part of one’s repertoire of biophysical analyses, when conducting characterizations of protein and other macromolecular interactions.

1 Perry JJ & Tainer JA. Developing advanced X-ray scattering methods combined with crystallography and computation. Methods. 2013 Mar;59(3):363-71.

Jeff (1)